Benzylamine analogues

ABSTRACT

A compound of the formula (I): wherein R&lt;SUP&gt;1 &lt;/SUP&gt;is a C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkyl group, an amino group, a (C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkyl)amino group, a di(C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkyl)amino group or a nitrogen-containing saturated heterocyclic group; R&lt;SUP&gt;3 &lt;/SUP&gt;is a hydrogen atom or a C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkyl group; Arom is an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group; wherein the substituted aryl group is substituted at 1 to 5 positions and the substituted heteroaryl group is substituted at 1 to 3 positions; and wherein the substituents of the aryl group and of the heteroaryl group are independently selected from the group consisting of halogen atom, C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkyl, halogeno C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkyl, C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkoxy, C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkylthio, C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;3 &lt;/SUB&gt;alkylenedioxy, C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;7 &lt;/SUB&gt;alkanoyl, C&lt;SUB&gt;2&lt;/SUB&gt;-C&lt;SUB&gt;7 &lt;/SUB&gt;alkyloxycarbonyl, amino, C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;7 &lt;/SUB&gt;alkanoylamino, hydroxyl, mercapto, cyano, nitro and carboxyl; A is a C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;6 &lt;/SUB&gt;alkylene group; R&lt;SUP&gt;a &lt;/SUP&gt;together with R&lt;SUP&gt;2 &lt;/SUP&gt;is a C&lt;SUB&gt;2&lt;/SUB&gt;-C&lt;SUB&gt;3 &lt;/SUB&gt;alkylene group containing a double bond; E is a single bond, an oxygen atom, a sulfur atom or a group of the formula: -NR&lt;SUP&gt;4&lt;/SUP&gt;-, wherein R&lt;SUP&gt;4 &lt;/SUP&gt;is a hydrogen atom or a C&lt;SUB&gt;1&lt;/SUB&gt;-C&lt;SUB&gt;7 &lt;/SUB&gt;alkanoyl group; X&lt;SUP&gt;1 &lt;/SUP&gt;and X&lt;SUP&gt;2 &lt;/SUP&gt;are the same or different and are an oxygen atom or a sulfur atom, or a pharmacologically acceptable salt or ester thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.10/629,108 filed Jul. 28, 2003, which is a continuation-in-partapplication of International Application PCT/JP02/00400 filed Jan. 22,2002, the entire contents of which are hereby incorporated by referenceherein.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to benzylamine analogues,pharmacologically acceptable salts or esters thereof and pharmaceuticalcompositions containing the same that have superior acetylcholinesteraseinhibitory action and selective serotonin reuptake inhibitory action,and which are useful as therapeutic or prophylactic drugs forAlzheimer's disease, depression, Huntington's chorea, Pick's disease,tardive dyskinesia, compulsive disorders or panic disorders.

2. Background Art

Given the rapid growth of the elderly population, there is an urgentdesire for the establishment of a treatment method for senile dementiaas typified by Alzheimer's disease, and research and development isbeing conducted on therapeutic drugs for Alzheimer's disease fromvarious perspectives. Since decreased acetylcholine concentration in thebrain and decreased cholinergic function are observed in Alzheimer'sdisease patients, studies have been conducted on the treatment ofAlzheimer's disease using acetylcholine precursor compounds,acetylcholinesterase inhibitors and acetylcholine agonists for thepurpose of activating cholinergic function. Activation of the centralcholinergic nervous system has been demonstrated to be effective for thetreatment of mild to moderate cases of Alzheimer's disease by clinicalapplication of acetylcholinesterase inhibitors (Rev. Contemp.Pharmacother., 6, 335 (1995)). Serious adverse side effects, namelyliver toxicity, which were observed with early acetylcholinesteraseinhibitors, have been improved considerably by ensuring inhibitoryaction specificity of the compounds to acetylcholinesterase andbutylcholinesterase, and second generation acetylcholinesteraseinhibitors are currently being developed (Neurology, 50, 136 (1998)).

Depression is frequently reported as a peripheral symptom in earlyAlzheimer's disease patients. Treatment using antidepressants has beentried, based on the idea that while impairment of cognitive function isstill mild, core symptoms such as cognitive function can be expected tobe improved by alleviating the depression (Ann. N.Y. Acad. Sci.,695,-254 (1993)). At present, the brain's serotonin system is widelyrecognized to be involved in depression. Research is being conducted ondrugs that act on serotonin receptors or serotonin reuptake inhibitors,and selective serotonin reuptake inhibitors have been reported to beantidepressants having minimal adverse side effects (Drugs, 32, 481(1986)). Drugs that are provided with both acetylcholinesteraseinhibitory action and selective serotonin reuptake inhibitor action areexpected to be able to alleviate depression and improve cognitivefunction, which are the core symptoms of Alzheimer's disease, and arethought to be more effective therapeutic drugs for Alzheimer's diseasethan compounds only having acetylcholinesterase inhibitory action.However, compounds having a similar chemical structure to the compoundsof the present invention that also have both acetylcholinesteraseinhibitory action and selective serotonin reuptake inhibitory actionhave heretofore not been known.

SUMMARY OF THE INVENTION

As a result of seeking to develop compounds having both superioracetylcholinesterase inhibitory action and selective serotonin reuptakeinhibitory action, and conducting earnest research over an extendedperiod of time on the synthesis of various benzene derivatives and theirpharmacological activity, the inventors of the present invention foundthat benzylamine analogues having an amine at the benzyl position haveboth superior acetylcholinesterase inhibitory action and selectiveserotonin reuptake inhibitory action, and are useful as therapeutic orprophylactic drugs (particularly therapeutic drugs) for Alzheimer'sdisease, depression, Huntington's chorea, Pick's disease, tardivedyskinesia, compulsive disorders or panic disorders (and particularlyAlzheimer's disease), thereby leading to completion of the presentinvention.

The novel benzylamine analogues of the present invention are compoundsof formula (I):

[wherein R¹ represents a C₁-C₆ alkyl group, an amino group, a (C₁-C₆alkyl)amino group, a di(C₁-C₆ alkyl)amino group or a nitrogen-containingsaturated heterocyclic group;

R² and R³ are the same or different and represent a hydrogen atom or aC₁-C₆ alkyl group;

Arom represents an aryl group, an aryl group substituted at from 1 to 5positions by substituent(s) which are the same or different selectedfrom the substituent group α, a heteroaryl group, or a heteroaryl groupsubstituted at from 1 to 3 positions by substituent(s) which are thesame or different selected from the substituent group α;

A represents a C₁-C₆ alkylene group;

R^(a) represents a hydrogen atom, a C₁-C₆ alkyl group or a C₂-C₆ alkenylgroup or, together with R², represents a C₁-C₃ alkylene group (in thecase of C₂-C₃, it may contain a double bond);

E represents a single bond, an oxygen atom, a sulfur atom or a group ofthe formula: —NR⁴— (wherein R⁴ represents a hydrogen atom or a C₁-C₇alkanoyl group);

X¹ and X² are the same or different and represent an oxygen atom or asulfur atom]

or a pharmacologically acceptable salt or ester thereof.

<Substituent Group α>

halogen atom, C₁-C₆ alkyl group, halogeno C₁-C₆ alkyl group, C₁-C₆alkoxy group, C₁-C₆ alkylthio group, C₁-C₃ alkylenedioxy group, C₁-C₇alkanoyl group, C₂-C₇ alkyloxycarbonyl group, amino group, C₁-C₇alkanoylamino group, hydroxyl group, mercapto group, cyano group, nitrogroup and carboxyl group.

DETAILED DESCRIPTION OF THE INVENTION

The compound of the above formula (I) or the pharmacologicallyacceptable salt or ester is preferably

(1) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)— is a carbamoyl group, a (C₁-C₄alkyl)carbamoyl group, a di(C₁-C₄ alkyl)carbamoyl group, a thiocarbamoylgroup, a (C₁-C₄ alkyl)thiocarbamoyl group or a di(C₁-C₄alkyl)thiocarbamoyl group,

(2) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)— is a (C₁-C₄ alkyl)carbamoylgroup, a di(C₁-C₄ alkyl)carbamoyl group, a (C₁-C₄ alkyl)thiocarbamoylgroup or a di(C₁-C₄ alkyl)thiocarbamoyl group,

(3) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)— is a (C₁-C₄ alkyl)carbamoyl groupor a di(C₁-C₄ alkyl)carbamoyl group,

(4) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)— is a di(C₁-C₄ alkyl)carbamoylgroup,

(5) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)— is a dimethylcarbamoyl group oran ethylmethylcarbamoyl group,

(6) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)— is a dimethylcarbamoyl group,

(7) a compound or pharmacologically acceptable salt or ester thereof inwhich R³ is a C₁-C₆ alkyl group,

(8) a compound or pharmacologically acceptable salt or ester thereof inwhich R³ is a methyl group or an ethyl group,

(9) a compound or pharmacologically acceptable salt or ester thereof inwhich R³ is a methyl group,

(10) a compound or pharmacologically acceptable salt or ester thereof inwhich R² is a hydrogen atom or a C₁-C₆ alkyl group,

(11) a compound or pharmacologically acceptable salt or ester thereof inwhich R² is a hydrogen atom, a methyl group or an ethyl group,

(12) a compound or pharmacologically acceptable salt or ester thereof inwhich R² is a hydrogen atom or a methyl group,

(13) a compound or pharmacologically acceptable salt or ester thereof inwhich R^(a), together with R², is a C₁-C₃ alkylene group which maycontain a double bond,

(14) a compound or pharmacologically acceptable salt or ester thereof inwhich R^(a), together with R², is a C₂-C₃ alkylene group which maycontain a double bond,

(15) a compound or pharmacologically acceptable salt or ester thereof inwhich R^(a) together with R², is a C₃ alkylene group which contains adouble bond,

(16) a compound or pharmacologically acceptable salt or ester thereof inwhich R^(a) is a hydrogen atom or a methyl group,

(17) a compound or pharmacologically acceptable salt or ester thereof inwhich R^(a) is a hydrogen atom,

(18) a compound or pharmacologically acceptable salt or ester thereof inwhich Arom is a phenyl group, a phenyl group substituted at from 1 to 3positions by substituent(s) which may be the same or different selectedfrom the substituent group α, a pyridyl group, or a pyridyl groupsubstituted at one position by a substituent selected from thesubstituent group α,

(19) a compound or pharmacologically acceptable salt or ester thereof inwhich Arom is a phenyl group or a phenyl group substituted at from 1 to3 positions by substituent(s) which may be the same or differentselected from the substituent group α,

(20) a compound or pharmacologically acceptable salt thereof in whichArom is a phenyl group substituted at one or two positions bysubstituent(s) which may be the same or different selected from thesubstituent group α1, or a phenyl group substituted at three positionsby halogen atoms,

(21) a compound or pharmacologically acceptable salt thereof in whichArom is a phenyl group substituted at one or two positions bysubstituent(s) which may be the same or different selected from thesubstituent group α2, or a phenyl group substituted at three positionsby fluorine atoms or chlorine atoms,

(22) a compound or pharmacologically acceptable salt thereof in whichArom is a phenyl group substituted at one or two positions bysubstituent(s) which may be the same or different selected from thesubstituent group α3, or a phenyl group substituted at three positionsby fluorine atoms,

(23) a compound or pharmacologically acceptable salt thereof in whichArom is a phenyl group substituted at one or two positions bysubstituent(s) which may be the same or different selected from thesubstituent group α4, or a phenyl group substituted at three positionsby fluorine atoms,

(24) a compound or pharmacologically acceptable salt thereof in whichArom is a phenyl group substituted at one position by a fluorine atom, achlorine atom or a nitro group, or a phenyl group substituted at twopositions by fluorine atoms,

(25) a compound or pharmacologically acceptable salt thereof in whichArom is a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-nitrophenylgroup or a 3,4-difluorophenyl group,

(26) a compound or pharmacologically acceptable salt or ester thereof inwhich A is a C₁-C₄ alkylene group,

(27) a compound or pharmacologically acceptable salt or ester thereof inwhich A is a methylene group or an ethylene group,

(28) a compound or pharmacologically acceptable salt or ester thereof inwhich A is an ethylene group,

(29) a compound or pharmacologically acceptable salt or ester thereof inwhich E is an oxygen atom or a single bond,

(30) a compound or pharmacologically acceptable salt or ester thereof inwhich E is an oxygen atom,

(31) a compound or pharmacologically acceptable salt or ester thereof inwhich X² is an oxygen atom,

(32) a compound or pharmacologically acceptable salt or ester thereof inwhich the group of formula: R¹—C(═X¹)—X²— is attached at thepara-position,

(33) a compound or pharmacologically acceptable salt or ester thereof inwhich R¹ is an amino group, a (C₁-C₆ alkyl)amino group or a di(C₁-C₆alkyl)amino group,

(34) a compound or pharmacologically acceptable salt or ester thereof inwhich R¹ is an amino group, a (C₁-C₄ alkyl)amino group or a di(C₁-C₄alkyl)amino group,

(35) a compound or pharmacologically acceptable salt or ester thereof inwhich R¹ is a (C₁-C₄ alkyl)amino group or a di(C₁-C₄ alkyl)amino group,

(36) a compound or pharmacologically acceptable salt or ester thereof inwhich X¹ is an oxygen atom,

<Substituent Group α1>

halogen atom, C₁-C₄ alkyl group, C₁-C₄ alkyl group substituted by from 1to 3 fluorine atoms, C₁-C₄ alkoxy group, C₁-C₄ alkylthio group,methylenedioxy group, ethylenedioxy group, C₁-C₄ alkanoyl group, cyanogroup and nitro group,

<Substituent Group α2>

fluorine atom, chlorine atom, methyl group, trifluoromethyl group,methoxy group, methylthio group, acetyl group, cyano group and nitrogroup,

<Substituent Group α3>

fluorine atom, chlorine atom, methylthio group, acetyl group, cyanogroup and nitro group,

<Substituent Group α4>

fluorine atom, chlorine atom, methylthio group and nitro group.

The pharmaceutical compositions of the present invention contain acompound of the above formula (I) or a pharmacologically acceptable saltor ester thereof as an active ingredient.

The inhibitors of acetylcholineesterase and selective serotonin reuptakeof the present invention contain a compound of the above formula (I) ora pharmacologically acceptable salt or ester thereof.

The therapeutic or prophylactic drugs for Alzheimer's disease,depression, Huntington's chorea, Pick's disease, tardive dyskinesia,compulsive disorders or panic disorders (preferably Alzheimer's disease)of the present invention contain a compound of the above formula (I) ora pharmacologically acceptable salt or ester thereof.

The “C₁-C₆ alkyl group” in R¹ to R³ and <substituent group α> in formula(I) may be a straight or branched chain alkyl group having from 1 to 6carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl and 2-ethylbutyl, and is preferably a straight orbranched chain alkyl group having from 1 to 4 carbon atoms, morepreferably a methyl group.

The “(C₁-C₆ alkyl)amino group” in R¹ in formula. (I) may be a straightor branched chain alkylamino group having from 1 to 6 carbon atoms suchas methylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino,2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino,isohexylamino, 4-methylpentylamino, 3-methylpentylamino,2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino,2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino,1,3-dimethylbutylamino, 2,3-dimethylbutylamino and 2-ethylbutylamino,and is preferably a methylamino group.

The “di(C₁-C₆ alkyl)amino group” in R¹ in the above formula (I) may be astraight or branched chain dialkylamino group having from 2 to 12 carbonatoms such as dimethylamino, diethylamino, ethylmethylamino,dipropylamino, diisopropylamino, dibutylamino, diisobutylamino,di-s-butylamino, di-tert-butylamino, dipentylamino, diisopentylamino,dineopentylamino, di-1-ethylpropylamino, dihexylamino anddiisohexylamino, and is preferably dimethylamino or ethylmethylamino,more preferably a dimethylamino group.

The “nitrogen-containing saturated heterocyclic group” in R¹ in theabove formula (I) may be a 5 to 7-membered saturated heterocyclic groupcontaining one nitrogen atom and from 0 to 3 sulfur atoms, oxygen atomsor/and nitrogen atoms such as morpholinyl, thiomorpholinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl andpiperazinyl, and is preferably a morpholinyl group.

Preferred groups for R¹ in the above formula (I) are (C₁-C₆ alkyl)aminogroups or di(C₁-C₆ alkyl)amino groups, more preferably di(C₁-C₆alkyl)amino groups.

The “aryl group” and the “aryl group” of the “aryl group substituted atfrom 1 to 5 positions by substituent.(s) which are the same or differentselected from the substituent group α” in Arom in the above formula (I)may be an aromatic hydrocarbon group having from 5 to 14 carbon atomssuch as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl, and ispreferably a phenyl group.

The “heteroaryl group” and the “heteroaryl group” of the. “heteroarylgroup substituted at from 1 to 3 positions by substituent(s) selectedfrom the substituent group α” in Arom in the above formula (I) may be a5 to 10-membered aromatic heterocyclic group containing from 1 to 3sulfur atoms, oxygen atoms and/or nitrogen atoms such as furyl, thienyl,pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl andquinolyl, and is preferably a pyridyl group.

The “C₁-C₆ alkylene group” in A in the above formula (I) may be astraight alkylene group having from 1 to 6 carbon atoms such asmethylene, ethylene, propylene, trimethylene, tetramethylene,pentamethylene and hexamethylene, and is preferably a straight alkylenegroup having from 1 to 4 carbon atoms, more preferably a methylene orethylene, further more preferably an ethylene group.

The “C₁-C₇ alkanoyl group” in R⁴ and <substituent group α> in the aboveformula (I) may be an alkylcarbonyl group having from 1 to 7 carbonatoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyland hexanoyl, and is preferably an acetyl group.

The preferred group for X¹ in the above formula (I) is an oxygen atom.

The “halogen atom” in <substituent group α> in the above formula (I) isa fluorine atom, a chlorine atom, a bromine atom or an iodine atom, andis preferably a fluorine atom or a chlorine atom.

The “halogeno C₁-C₆ alkyl group” in <substituent group α> in the aboveformula (I) means a group in which the “C₁-C₆ alkyl group” issubstituted by halogen atom(s) and may be a trifluoromethyl,trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl,2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl,4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl, and is preferably atrifluoromethyl group.

The “C₁-C₆ alkoxy group” in <substituent group α> in the above formula(I) indicates a group in which the above “C₁-C₆ alkyl group” is bondedto an oxygen atom and is a straight or branched chain alkoxy grouphaving from 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy,isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy,3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy,2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,1,3-dimethylbutoxy and 2,3-dimethylbutoxy, and is preferably a methoxygroup.

The “C₁-C₆ alkylthio group” in R^(a) and <substituent group α> in theabove formula (I) indicates a group in which the above “C₁-C₆ alkylgroup” is bonded to a sulfur atom and is a straight or branched chainalkylthio group having from 1 to 6 carbon atoms such as methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio,s-butylthio, tert-butylthio, n-pentylthio, isopentylthio,2-methylbutylthio, neopentylthio, 1-ethylpropylthio, n-hexylthio,isohexylthio, 4-methylpentylthio, 3-methylpentylthio,2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio,2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio,1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio, andis preferably a methylthio group.

The “C₁-C₃ alkylene group which may contain a double bond” for R^(a) andR² in the above formula (I) indicates a straight or branched chainalkylene group having from 1 to 3 carbon atoms which may contain adouble bond such as methylene, methylmethylene, ethylene, propylene,trimethylene, vinylene or propynylene, and is preferably a straight orbranched chain alkylene group having 2 or 3 carbon atoms which maycontain a double bond, more preferably a propynylene group.

The “C₁-C₃ alkylenedioxy group” in <substituent group α> in the aboveformula (I) indicates methylenedioxy, ethylenedioxy or propylenedioxy,and is preferably a methylenedioxy group.

The “C₂-C₇ alkyloxycarbonyl group” in <substituent group α> in the aboveformula (I) may be an alkyloxycarbonyl group having from 2 to 7 carbonatoms such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl andisobutoxycarbonyl, and is preferably a methoxycarbonyl group.

The “C₁-C₇ alkanoylamino group” in <substituent group α> in the aboveformula (I) indicates a group in which the “C₁-C₇ alkanoyl group” issubstituted by an amino group and may be an alkylcarbonylamino grouphaving from 1 to 7 carbon atoms such as formylamino, acetylamino,propionylamino, butyrylamino, isobutyrylamino and pentanoylamino, and ispreferably an acetylamino group.

In the above, the “ester thereof” indicates an ester, since thecompounds of the present invention can be made into esters, and thisester indicates an “ester of a hydroxyl group” and an “ester of acarboxyl group” and means an ester in which the ester residue is a“general protecting group” or a “protecting group which is cleavable bychemical or enzymatic hydrolysis in vivo”.

The “general protecting group” is a protecting group which is cleavableby a chemical process such as hydrogenolysis, hydrolysis, electrolysisand photolysis. The “general protecting group” relating to the “ester ofa hydroxyl group” may be an “aliphatic acyl group” such as analkylcarbonyl group, e.g., formyl, acetyl, propionyl, butyryl,isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl,nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl,15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl,nonadecanoyl, eicosanoyl and heneicosanoyl; a carboxylated alkylcarbonylgroup, e.g., succinoyl, glutaroyl and adipoyl; a lower alkylcarbonylgroup substituted by one or more halogen atoms, e.g., chloroacetyl,dichloroacetyl, trichloroacetyl and trifluoroacetyl; a saturated cyclichydrocarbon-carbonyl group, e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,cycloheptylcarbonyl and cyclooctylcarbonyl; a lower alkoxy loweralkylcarbonyl group, e.g., methoxyacetyl; or an unsaturatedalkylcarbonyl group, e.g., (E)-2-methyl-2-butenoyl; an “aromatic acylgroup” such as an arylcarbonyl group e.g., benzoyl, naphthoyl, pyridoyl,thienoyl and furoyl; an arylcarbonyl group substituted by one or morehalogen atoms, e.g., 2-bromobenzoyl and 4-chlorobenzoyl; a loweralkylated arylcarbonyl group, e.g., 2,4,6-trimethylbenzoyl and4-toluoyl; a lower alkoxylated arylcarbonyl group, e.g. 4-anisoyl; acarboxylated arylcarbonyl group, e.g., 2-carboxybenzoyl,3-carboxybenzoyl and 4-carboxybenzoyl; a nitrated arylcarbonyl group,e.g., 4-nitrobenzoyl and 2-nitrobenzoyl; a lower alkoxycarbonylatedarylcarbonyl group, e.g., 2-(methoxycarbonyl)benzoyl; or an arylatedarylcarbonyl group, e.g., 4-phenylbenzoyl; an “aralkylcarbonyl group”such as a lower alkylcarbonyl group substituted with from 1 to 3 arylgroups, e.g., phenylacetyl, α-naphthylpropionyl, β-naphthylbutyryl,diphenylisobutyryl, triphenylacetyl, α-naphthyldiphenylisobutyryl and9-anthrylpentanoyl; or a lower alkylcarbonyl group which is substitutedwith from 1 to 3 aryl groups in which said aryl moiety is substitutedwith lower alkyl group(s), lower alkoxy group(s), nitro group(s),halogen atom(s) and/or cyano group(s), e.g., 4-methylphenylacetyl,2,4,6-trimethylphenylformyl, 3,4,5-trimethylphenylbutyryl,4-methoxyphenylisobutyryl, 4-methoxyphenyldiphenylpivaloyl,2-nitrophenylacetyl, 4-nitrophenylpropionyl, 4-chlorophenylbutyryl,4-bromophenylacetyl and 4-cyanophenylpentanoyl; a “tetrahydropyranyl ortetrahydrothiopyranyl group” such as tetrahydropyran-2-yl,3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl,tetrahydrothiopyran-2-yl, and 4-methoxytetrahydrothiopyran-4-yl; a“tetrahydrofuranyl or tetrahydrothiofuranyl group” such astetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl; a “silyl group” suchas a tri(lower alkyl)silyl group e.g., trimethylsilyl, triethylsilyl,isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl,methyl di-t-butylsilyl and triisopropylsilyl; or a tri(lower alkyl)silylgroup which is substituted with one or two aryl groups, e.g.,diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl andphenyldiisopropylsilyl; an “alkoxymethyl group” such as a loweralkoxymethyl group, e.g., methoxymethyl, 1,1-dimethyl-1-methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl andt-butoxymethyl; a lower alkoxylated lower alkoxymethyl group, e.g.,2-methoxyethoxymethyl; or a lower alkoxymethyl group which issubstituted with one or more halogen atoms, e.g.,2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; a“substituted ethyl group” such as a lower alkoxylated ethyl group, e.g.,1-ethoxyethyl-1-(isopropoxy)ethyl; or a halogenated ethyl group, e.g.,2,2,2-trichloroethyl; an “aralkyl group” such as a lower alkyl groupwhich is substituted with from 1 to 3 aryl groups, e.g., benzyl,α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl,α-naphthyldiphenylmethyl and 9-anthrylmethyl; or a lower alkyl groupwhich is substituted with from 1 to 3 aryl groups in which said arylmoiety is substituted with lower alkyl group(s), lower alkoxy group(s),nitro group(s), halogen atom(s) and/or cyano group(s), e.g.,4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl,4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl,4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; an“alkoxycarbonyl group” such as a lower alkoxycarbonyl group, e.g.,methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl;or a lower alkoxycarbonyl group which is substituted with halogenatom(s) and/or tri(lower alkyl)silyl group(s), e.g.,2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; an“alkenyloxycarbonyl group” such as vinyloxycarbonylallyloxycarbonyl; oran “aralkyloxycarbonyl group” in which the aryl moiety may besubstituted with one or two lower alkoxy groups and/or nitro groups suchas benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and4-nitrobenzyloxycarbonyl.

On the other hand, the “general protecting group” relating to the “esterof a carboxyl group” may preferably be a “lower alkyl group” such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and2-ethylbutyl; an “alkenyl group” such as ethenyl, 1-propenyl,2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl,2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl,1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl,2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and5-hexenyl; an “alkynyl group” such as ethynyl, 2-propynyl,1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl,1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl,1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl,1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,4-hexynyl and 5-hexynyl; a “lower alkyl group which is substituted withone or more halogen atoms” such as trifluoromethyl, trichloromethyl,difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl,2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyland 2,2-dibromoethyl; a “hydroxy lower alkyl group” such as2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyland 4-hydroxybutyl; an “aliphatic acyl”-“lower alkyl group” such asacetylmethyl; an “aralkyl group” such as a lower alkyl group which issubstituted with from 1 to 3 aryl groups e.g., benzyl, phenethyl,3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl,triphenylmethyl, 6-phenylhexyl, α-naphthyldiphenylmethyl and9-anthrylmethyl; or a lower alkyl group which is substituted with from 1to 3 aryl groups in which said aryl moiety is substituted with loweralkyl group(s), lower alkoxy group(s), nitro group(s), halogen atom(s),cyano group(s) and/or alkoxycarbonyl group(s), e.g., 4-methylbenzyl,2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl,4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl,4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, piperonyl and4-methoxycarbonylbenzyl; or a “silyl group” such as trimethylsilyl,triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,methyldiisopropylsilyl, methyl di-t-butylsilyl, triisopropylsilyl,methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl andphenyldiisopropylsilyl.

The “protecting group which is cleavable by chemical or enzymatichydrolysis in vivo” means a protecting group which is cleavable by abiological method such as hydrolysis in the human body to produce a freeacid or a salt thereof. The suitability of such a derivative can bedetermined by administering it to an experimental animal such as a rator a mouse by an intravenous injection, measuring a body fluid of theanimal thereafter and detecting the original compound or apharmacologically acceptable salt thereof.

The “protecting group which is cleavable by chemical or enzymatichydrolysis in vivo” relating to the “ester of a hydroxyl group” may be a1-(acyloxy) “lower alkyl group” such as a 1-(“aliphatic acylfoxy) “loweralkyl group”, e.g., formyloxymethyl, acetoxymethyl,dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl,hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl,1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl,1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl,1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl,1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl,1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl,1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl,1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl,1-pivaloyloxypentyl and 1-pivaloyloxyhexyl; a 1-(“aliphatic acyl” thio)“lower alkyl group”, e.g., formylthiomethyl, acetylthiomethyl,dimethylaminoacetylthiomethyl, propionylthiomethyl, butyrylthiomethyl,pivaloylthiomethyl, valerylthiomethyl, isovalerylthiomethyl,hexanoylthiomethyl, 1-formylthioethyl, 1-acetylthioethyl,1-propionylthioethyl, 1-butyrylthioethyl, 1-pivaloylthioethyl,1-valerylthioethyl, 1-isovalerylthioethyl, 1-hexanoylthioethyl,1-formylthiopropyl, 1-acetylthiopropyl, 1-propionylthiopropyl,1-butyrylthiopropyl, 1-pivaloylthiopropyl, 1-valerylthiopropyl,1-isovalerylthiopropyl, 1-hexanoylthiopropyl, 1-acetylthiobutyl,1-propionylthiobutyl, 1-butyrylthiobutyl, 1-pivaloylthiobutyl,1-acetylthiopentyl, 1-propionylthiopentyl, 1-butyrylthiopentyl,1-pivaloylthiopentyl and 1-pivaloylthiohexyl; a 1-(“cycloalkyl”carbonyloxy) “lower alkyl group”, e.g., cyclopentylcarbonyloxymethyl,cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl,1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl,1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and1-cyclohexylcarbonyloxybutyl; or a 1-(“aromatic acyl” oxy) “lower alkylgroup” such as benzoyloxymethyl; an (alkoxycarbonyloxy)alkyl group suchas methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl,pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl,cyclohexyloxycarbonyloxymethyl,cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl,1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl,1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl,1-(isobutoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl),1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl,1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl,1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl,1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl,1-(ethoxycarbonyloxy)propyl, 2-(methoxycarbonyloxy)ethyl,2-(ethoxycarbonyloxy)ethyl, 2-(propoxycarbonyloxy)ethyl,2-(isopropoxycarbonyloxy)ethyl, 2-(butoxycarbonyloxy)ethyl,2-(isobutoxycarbonyloxy)ethyl, 2-(pentyloxycarbonyloxy)ethyl,2-(hexyloxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl,1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl,1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl,1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl,1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl,1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl,1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl,1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl,1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and1-(ethoxycarbonyloxy)hexyl; a “phthalidyl group” such as phthalidyl,dimethylphthalidyl and dimethoxyphthalidyl; a “carbonyloxyalkyl group”such as an oxodioxolenylmethyl group, e.g.,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-chlorophenyl-2-oxo-1,3-dioxolen-4-yl)methyl,(2-oxo-1,3-dioxolen-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; the above “aliphatic acylgroup”; the above “aromatic acyl group” a “half ester salt residualgroup of succinic acid”; a “phosphoric acid ester salt residual group”;an “ester forming residual group such as an amino acid”; a carbamoylgroup; a carbamoyl group substituted by one or two lower alkyl groups; acarboxy “lower alkyl” dithioethyl group such as2-carboxyethyldithioethyl, 3-carboxypropyldithioethyl,4-carboxybutyldithioethyl, 5-carboxypentyldithioethyl and6-carboxyhexyldithioethyl; or a “lower alkyl group” dithioethyl groupsuch as methyldithioethyl, ethyldithioethyl, propyldithioethyl,butyldithioethyl, pentyldithioethyl and hexyldithioethyl.

On the other hand, the “protecting group which is cleavable by chemicalor enzymatic hydrolysis in vivo” relating to the “ester of a carboxylgroup” may specifically be an “alkoxy lower alkyl group” such as a loweralkoxy lower alkyl group, e.g., methoxymethyl, 1-ethoxyethyl,1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl,2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl; alower alkoxylated lower alkoxy lower alkyl group, e.g.2-methoxyethoxymethyl; an “aryl group” oxy “lower alkyl group”, e.g.,phenoxymethyl; or a halogenated lower alkoxy lower alkyl group, e.g.,2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; a “loweralkoxy” carbonyl “lower alkyl group” such as methoxycarbonylmethyl; acyano “lower alkyl group” such as cyanomethyl and 2-cyanoethyl; a “loweralkyl group” thiomethyl group such as methylthiomethyl andethylthiomethyl; an “aryl group” thiomethyl group such asphenylthiomethyl and naphthylthiomethyl; a “lower alkyl group” sulfonyl“lower alkyl group” which may be substituted by halogen atom(s) such as2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl; an “arylgroup” sulfonyl “lower alkyl group” such as 2-benzenesulfonylethyl and2-toluenesulfonylethyl; an acyloxy “lower alkyl group” such as an“aliphatic acyl” oxy “lower alkyl group”, e.g., formyloxymethyl,acetoxymethyl, propionylbxymethyl, butyryloxymethyl, pivaloyloxymethyl,valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl,1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl,1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl,1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl,2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl,2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl,2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl,1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl,1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl,1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl,1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl,1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl; a“cycloalkyl” carbonyloxy “lower alkyl group”, e.g.,cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl,1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl,1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl,1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl; or an“aromatic acyl” oxy “lower alkyl group”, e.g., benzoyloxymethyl; an(alkoxycarbonyloxy)alkyl group such as methoxycarbonyloxymethyl,ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl,hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl,cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl,1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl,1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl,1-(isobutoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl,1-(pentyloxycarbornyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl,1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl,1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl.,1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl,1-(ethoxycarbonyloxy)propyl, 2-(methoxycarbonyloxy)ethyl,2-(ethoxycarbonyloxy)ethyl, 2-(propoxycarbonyloxy)ethyl,2-(isopropoxycarbonyloxy)ethyl, 2-(butoxycarbonyloxy)ethyl,2-(isobutoxycarbonyloxy)ethyl, 2-(pentyloxycarbonyloxy)ethyl,2-(hexyloxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl,1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl,1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl,1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl,1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl,1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl,1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl,1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl,1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)pentyl,1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and1-(ethoxycarbonyloxy)hexyl; a “carbonyloxyalkyl group” such as anoxodioxolenylmethyl group, e.g.,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(2-oxo-1,3-dioxolen-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; a “phthalidyl group” such asphthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; an “aryl group”such as phenyl and indanyl; the above “lower alkyl group”; the above“alkylthio group”; a “carboxy group alkyl group” such as carboxyl groupmethyl; or an “amide forming residual group of an amino acid” such asphenylalanine.

In the compound (I) of the present invention, while optical isomers(including diastereomers) based on asymmetrical carbon atom(s) in themolecule exist, and geometric isomers based on a ring structuresometimes exist, these respective isomers are included in the presentinvention.

The “pharmacologically acceptable salt thereof” means a salt since thecompound (I) of the present invention can be converted into salts, andthese salts may preferably be a metal salt such as an alkali metal salt,e.g., a sodium salt, a potassium salt and a lithium salt; a alkalineearth metal salt, e.g., a calcium salt and a magnesium salt; an aluminumsalt; an iron salt; a zinc salt; a copper salt; a nickel salt; or acobalt salt; an amine salt such as an inorganic salt, e.g., an ammoniumsalt; or an organic salt, e.g., a t-octylamine salt, a dibenzylaminesalt, a morpholine salt, a glucosamine salt, a phenylglycinealkyl estersalt, an ethylenediamine salt, a N-methylglucamine salt, a guanidinesalt, a diethylamine salt, a triethylamine salt, a dicyclohexylaminesalt, a N,N′-dibenzylethylenediamine salt, a chloroprocaine salt, aprocaine salt, a diethanolamine salt, a N-benzyl-phenethylamine salt, apiperazine salt, a tetramethylammonium salt and atris(hydroxymethyl)aminomethane salt; an inorganic acid salt such as ahydrogen halide salt, e.g., hydrofluoride, hydrochloride, hydrobromideand hydroiodide; nitrate; perchlorate; sulfate; or phosphate; an organicacid salt such as a lower alkanesulfonate, e.g., methanesulfonate,trifluoromethanesulfonate and ethanesulfonate; a arylsulfonate, e.g.,benzenesulfonate and p-toluenesulfonate; acetate; malate; fumarate;succinate; citrate; tartrate; oxalate; or maleate; an amino acid saltsuch as glycine salt, lysine salt, arginine salt, ornithine salt,glutamate and aspartate; and are more preferably an inorganic acid salt.

The compound (I) of the present invention can also exist as a hydrate.

Compounds shown in the following Table 1 to Table 5 are specificallyillustrated as preferred compounds of formula (I). However, the compoundof the present invention is not limited to these.

The meaning of the abbreviations in the following Table 1 to Table 5 isshown below. That is,

-   Ac represents an acetyl group,-   tBu represents a t-butyl group,-   Car represents a carbamoyl group,-   diMeCar represents a N,N-dimethylcarbamoyl group,-   diMeTcr represents a N,N-dimethylthiocarbamoyl group,-   diEtCar represents a N,N-diethylcarbamoyl group,-   diPrCar represents a N,N-diisopropylcarbamoyl group,-   MeEtCar represents a N-methyl-N-ethylcarbamoyl group,-   Et represents an ethyl group,-   Me represents a methyl group,-   diMeN represents a dimethylamino group,-   MeEtN represents a methylethylamino group,-   MeOCO represents a methoxycarbonyl group,-   Mor represents a morpholino group,-   Mtdo represents a methylenedioxy group,-   pentaFPH represents a pentafluorophenyl group,-   Ph represents a phenyl group,-   Pr represets a propyl group,-   iPr represents an isopropyl group,-   Py-2-yl represents a pyridin-2-yl group,-   Py-3-yl represents a pyridin-3-yl group,-   Py-4-yl represents a pyridin-4-yl group, and

Thi-3-yl represents a thiophen-3-yl group. TABLE 1 (Ia)

Com- pound No. R¹—(C═X¹) R²R³N A E Arom 1-1 diMeCar MeNH (CH₂)₂ — 4-F—Ph1-2 EtCar MeNH (CH₂)₂ — 4-F—Ph 1-3 EtCar MeNH (CH₂)₂ — 4-MeO—Ph 1-4 AcMeNH (CH₂)₂ — 4-F—Ph 1-5 tBu-(C═O) MeNH (CH₂)₂ — 4-F—Ph 1-6 diEtCar MeNH(CH₂)₂ — 4-F—Ph 1-7 diEtCar MeNH (CH₂)₂ O 4-Cl—Ph 1-8 diEtCar MeNH(CH₂)₂ O 3-Cl—Ph 1-9 diPrCar MeNH (CH₂)₂ — 4-F—Ph 1-10 MeEtCar MeNH(CH₂)₂ O 4-Cl—Ph 1-11 Mor-(C═O) MeNH (CH₂)₂ — 4-F—Ph 1-12 diMeTcr MeNH(CH₂)₂ — 4-F—Ph 1-13 diMeCar MeNH (CH₂)₂ — 4-Cl—Ph 1-14 diMeCar MeNH(CH₂)₂ — 4-CF₃—Ph 1-15 diMeCar MeNH (CH₂)₂ — 4-MeO—Ph 1-16 diMeCar diMeN(CH₂)₂ — 4-MeO—Ph 1-17 diMeCar MeNH (CH₂)₂ — 3-MeO-4-MeO—Ph 1-18 diMeCarMeNH (CH₂)₂ — 3,4-Mtdo—Ph 1-19 diMeCar MeNH (CH₂)₂ — 4-NO₂—Ph 1-20diMeCar MeNH (CH₂)₂ — 3-F-4-F—Ph 1-21 diMeCar diMeN (CH₂)₂ — 4-F—Ph 1-22diMeCar diMeN (CH₂)₂ — 4-Cl—Ph 1-23 diMeCar diMeN (CH₂)₂ — 4-NO₂—Ph 1-24diMeCar diMeN (CH₂)₂ — 3-F-4-F—Ph 1-25 diMeCar MeNH (CH₂)₃ — 4-F—Ph 1-26diMeCar MeNH (CH₂)₃ — 4-Cl—Ph 1-27 diMeCar MeNH (CH₂)₃ — 4-NO₂—Ph 1-28diMeCar MeNH (CH₂)₃ — 3-F-4-F—Ph 1-29 diMeCar diMeN (CH₂)₃ — 4-F—Ph 1-30diMeCar diMeN (CH₂)₃ — 4-Cl—Ph 1-31 diMeCar diMeN (CH₂)₃ — 4-NO₂—Ph 1-32diMeCar diMeN (CH₂)₃ — 3-F-4-F—Ph 1-33 diMeCar MeNH CH₂ O 4-F—Ph 1-34diMeCar MeNH CH₂ O 4-Cl—Ph 1-35 diMeCar MeNH CH₂ O 4-NO₂—Ph 1-36 diMeCarMeNH CH₂ O 3-F-4-F—Ph 1-37 diMeCar diMeN CH₂ O 4-F—Ph 1-38 diMeCar diMeNCH₂ O 4-Cl—Ph 1-39 diMeCar diMeN CH₂ O 4-NO₂—Ph 1-40 diMeCar diMeN CH₂ O3-F-4-F—Ph 1-41 diMeCar MeNH (CH₂)₂ S 4-F—Ph 1-42 diMeCar MeNH (CH₂)₂ S4-Cl—Ph 1-43 diMeCar MeNH (CH₂)₂ S 4-NO₂—Ph 1-44 diMeCar MeNH (CH₂)₂ S3-F-4-F—Ph 1-45 diMeCar diMeN (CH₂)₂ S 4-F—Ph 1-46 diMeCar diMeN (CH₂)₂S 4-Cl—Ph 1-47 diMeCar diMeN (CH₂)₂ S 4-NO₂—Ph 1-48 diMeCar diMeN (CH₂)₂S 3-F-4-F—Ph 1-49 diMeCar MeNH (CH₂)₂ NH 4-F—Ph 1-50 diMeCar MeNH (CH₂)₂NH 4-Cl—Ph 1-51 diMeCar MeNH (CH₂)₂ NH 3-F—Ph 1-52 diMeCar MeNH (CH₂)₂NH 3-Cl—Ph 1-53 diMeCar MeNH (CH₂)₂ NH 4-NO₂—Ph 1-54 diMeCar MeNH (CH₂)₂NH 3-F-4-F—Ph 1-55 diMeCar diMeN (CH₂)₂ NH 4-F—Ph 1-56 diMeCar diMeN(CH₂)₂ NH 4-Cl—Ph 1-57 diMeCar diMeN (CH₂)₂ NH 4-NO₂—Ph 1-58 diMeCardiMeN (CH₂)₂ NH 3-F-4-F—Ph 1-59 diMeCar MeNH (CH₂)₂ NAc 4-Cl—Ph 1-60diMeCar MeNH (CH₂)₂ NAc 3-F—Ph 1-61 diMeCar MeNH (CH₂)₂ NAc 4-NO₂—Ph1-62 diMeCar diMeN (CH₂)₂ NAc 4-Cl—Ph 1-63 diMeCar diMeN (CH₂)₂ NAc3-F—Ph 1-64 diMeCar diMeN (CH₂)₂ NAc 4-NO₂—Ph 1-65 diMeCar NH₂ (CH₂)₂ O4-F—Ph 1-66 diMeCar NH₂ (CH₂)₂ O 4-NO₂—Ph 1-67 diMeCar EtNH (CH₂)₂ O4-F—Ph 1-68 diMeCar EtNH (CH₂)₂ O 3-F—Ph 1-69 diMeCar EtNH (CH₂)₂ O4-Cl—Ph 1-70 diMeCar EtNH (CH₂)₂ O 3-NO₂—Ph 1-71 diMeCar EtNH (CH₂)₂ O4-NO₂—Ph 1-72 diMeCar EtNH (CH₂)₂ O 3-F-4-F—Ph 1-73 diMeCar PrNH (CH₂)₂O 4-F—Ph 1-74 diMeCar MeNH (CH₂)₂ O Ph 1-75 diMeCar MeNH (CH₂)₂ O 4-F—Ph1-76 diMeCar MeNH (CH₂)₂ O 3-F—Ph 1-77 diMeCar MeNH (CH₂)₂ O 2-F—Ph 1-78diMeCar MeNH (CH₂)₂ O 4-Cl—Ph 1-79 diMeCar MeNH (CH₂)₂ O 3-Cl—Ph 1-80diMeCar MeNH (CH₂)₂ O 2-Cl—Ph 1-81 diMeCar MeNH (CH₂)₂ O 4-Br—Ph 1-82diMeCar MeNH (CH₂)₂ O 4-Me—Ph 1-83 diMeCar MeNH (CH₂)₂ O 3-Me—Ph 1-84diMeCar MeNH (CH₂)₂ O 2-Me—Ph 1-85 diMeCar MeNH (CH₂)₂ O 4-CF3—Ph 1-86diMeCar MeNH (CH₂)₂ O 4-MeO—Ph 1-87 diMeCar MeNH (CH₂)₂ O 3-MeO—Ph 1-88diMeCar MeNH (CH₂)₂ O 2-MeO—Ph 1-89 diMeCar MeNH (CH₂)₂ O 4-Ac—Ph 1-90diMeCar MeNH (CH₂)₂ O 3-Ac—Ph 1-91 diMeCar MeNH (CH₂)₂ O 4-CN—Ph 1-92diMeCar MeNH (CH₂)₂ O 4-NO₂—Ph 1-93 diMeCar MeNH (CH₂)₂ O 2-NO₂—Ph 1-94diMeCar MeNH (CH₂)₂ O 3-NO₂—Ph 1-95 diMeCar MeNH (CH₂)₂ O 4-NH₂—Ph 1-96diMeCar MeNH (CH₂)₂ O 3-NH₂—Ph 1-97 diMeCar MeNH (CH₂)₂ O 4-AcNH—Ph 1-98diMeCar MeNH (CH₂)₂ O 3-AcNH—Ph 1-99 diMeCar MeNH (CH₂)₂ O 4-COOH—Ph1-100 diMeCar MeNH (CH₂)₂ O 3,4-Mtdo-Ph 1-101 diMeCar MeNH (CH₂)₂ O2-F-4-F—Ph 1-102 diMeCar MeNH (CH₂)₂ O 3-F-4-F—Ph 1-103 diMeCar MeNH(CH₂)₂ O 3-F-s-F—Ph 1-104 diMeCar MeNH (CH₂)₂ O 3-F-4-Cl—Ph 1-105diMeCar MeNH (CH₂)₂ O 2-F-4-NO₂—Ph 1-106 diMeCar MeNH (CH₂)₂ O2-Cl-4-F—Ph 1-107 diMeCar MeNH (CH₂)₂ O 2-Cl-4-Cl—Ph 1-108 diMeCar MeNH(CH₂)₂ O 2-Cl-4-NO₂—Ph 1-109 diMeCar MeNH (CH₂)₂ O 3-Cl-4-F—Ph 1-110diMeCar MeNH (CH₂)₂ O 3-Cl-4-Cl—Ph 1-111 diMeCar MeNH (CH₂)₂ O2-Me-4-F—Ph 1-112 diMeCar MeNH (CH₂)₂ O 2-Me-4-Cl—Ph 1-113 diMeCar MeNH(CH₂)₂ O 3-Me-4-Cl—Ph 1-114 diMeCar MeNH (CH₂)₂ O 3-Me-4-Me—Ph 1-115diMeCar MeNH (CH₂)₂ O 3-Me-4-NO₂—Ph 1-116 diMeCar MeNH (CH₂)₂ O3-NO₂-4-Cl—Ph 1-117 diMeCar MeNH (CH₂)₂ O 3-F-4-F-5-F—Ph 1-118 diMeCarMeNH (CH₂)₂ O 2-F-3-F-5-F—Ph 1-119 diMeCar MeNH (CH₂)₂ O Py-3-yl 1-120diMeCar MeNH (CH₂)₂ O 5-Cl—Py-3-yl 1-121 diMeCar MeNH (CH₂)₂ O2-Me—Py-3-yl 1-122 diMeCar MeNH (CH₂)₂ O 6-Me—Py-3-yl 1-123 diMeCar MeNH(CH₂)₂ O Py-2-yl 1-124 diMeCar MeNH (CH₂)₂ O 6-Cl—Py-2-yl 1-125 diMeCarMeNH (CH₂)₂ O 6-CF₃—Py-2-yl 1-126 diMeCar MeNH (CH₂)₂ O 6-NO₂—Py-2-yl1-127 diMeCar MeNH (CH₂)₂ O Py-4-yl 1-128 diMeCar MeNH (CH₂)₂ O2-NO₂—Py-4-yl 1-129 diMeCar MeNH (CH₂)₂ O Thi-3-yl 1-130 diMeCar MeNH(CH₂)₂ O 2-MeOCO-Thi-3-yl 1-131 diMeCar diMeN (CH₂)₂ O Ph 1-132 diMeCardiMeN (CH₂)₂ O 4-F—Ph 1-133 diMeCar diMeN (CH₂)₂ O 3-F—Ph 1-134 diMeCardiMeN (CH₂)₂ O 2-F—Ph 1-135 diMeCar diMeN (CH₂)₂ O 4-Cl—Ph 1-136 diMeCardiMeN (CH₂)₂ O 3-Cl—Ph 1-137 diMeCar diMeN (CH₂)₂ O 2-Cl—Ph 1-138diMeCar diMeN (CH₂)₂ O 4-Br—Ph 1-139 diMeCar diMeN (CH₂)₂ O 4-Me—Ph1-140 diMeCar diMeN (CH₂)₂ O 3-Me—Ph 1-141 diMeCar diMeN (CH₂)₂ O2-Me—Ph 1-142 diMeCar diMeN (CH₂)₂ O 4-CF₃—Ph 1-143 diMeCar diMeN (CH₂)₂O 4-MeO—Ph 1-144 diMeCar diMeN (CH₂)₂ O 3-MeO—Ph 1-145 diMeCar diMeN(CH₂)₂ O 2-MeO—Ph 1-146 diMeCar diMeN (CH₂)₂ O 4-Ac—Ph 1-147 diMeCardiMeN (CH₂)₂ O 3-Ac—Ph 1-148 diMeCar diMeN (CH₂)₂ O 4-CN—Ph 1-149diMeCar diMeN (CH₂)₂ O 4-NO₂—Ph 1-150 diMeCar diMeN (CH₂)₂ O 2-NO₂—Ph1-151 diMeCar diMeN (CH₂)₂ O 3-NO₂—Ph 1-152 diMeCar diMeN (CH₂)₂ O4-NH₂—Ph 1-153 diMeCar diMeN (CH₂)₂ O 3-NH₂—Ph 1-154 diMeCar diMeN(CH₂)₂ O 4-AcNH—Ph 1-155 diMeCar diMeN (CH₂)₂ O 3-AcNH—Ph 1-156 diMeCardiMeN (CH₂)₂ O 4-COOH—Ph 1-157 diMeCar diMeN (CH₂)₂ O 3,4-Mtdo-Ph 1-158diMeCar diMeN (CH₂)₂ O 2-F-4-F—Ph 1-159 diMeCar diMeN (CH₂)₂ O3-F-4-F—Ph 1-160 diMeCar diMeN (CH₂)₂ O 3-F-5-F—Ph 1-161 diMeCar diMeN(CH₂)₂ O 3-F-4-Cl—Ph 1-162 diMeCar diMeN (CH₂)₂ O 2-F-4-NO₂—Ph 1-163diMeCar diMeN (CH₂)₂ O 2-Cl-4-F—Ph 1-164 diMeCar diMeN (CH₂)₂ O2-Cl-4-Cl—Ph 1-165 diMeCar diMeN (CH₂)₂ O 2-Cl-4-NO₂—Ph 1-166 diMeCardiMeN (CH₂)₂ O 3-Cl-4-F—Ph 1-167 diMeCar diMeN (CH₂)₂ O 3-Cl-4-Cl—Ph1-168 diMeCar diMeN (CH₂)₂ O 2-Me-4-F—Ph 1-169 diMeCar diMeN (CH₂)₂ O2-Me-4-Cl—Ph 1-170 diMeCar diMeN (CH₂)₂ O 3-Me-4-Cl—Ph 1-171 diMeCardiMeN (CH₂)₂ O 3-Me-4-Me—Ph 1-172 diMeCar diMeN (CH₂)₂ O 3-Me-4-NO₂—Ph1-173 diMeCar diMeN (CH₂)₂ O 3-NO₂-4-Cl—Ph 1-174 diMeCar diMeN (CH₂)₂ O3-F-4-F-5-F—Ph 1-175 diMeCar diMeN (CH₂)₂ O 2-F-3-F-5-F—Ph 1-176 diMeCardiMeN (CH₂)₂ O Py-3-yl 1-177 diMeCar diMeN (CH₂)₂ O 5-Cl—Py-3-yl 1-178diMeCar diMeN (CH₂)₂ O 2-Me—Py-3-yl 1-179 diMeCar diMeN (CH₂)₂ O6-Me—Py-3-yl 1-180 diMeCar diMeN (CH₂)₂ O Py-2-yl 1-181 diMeCar diMeN(CH₂)₂ O 6-Cl—Py-2-yl 1-182 diMeCar diMeN (CH₂)₂ O 6-CF₃—Py-2-yl 1-183diMeCar diMeN (CH₂)₂ O 6-NO₂—Py-2-yl 1-184 diMeCar diMeN (CH₂)₂ OPy-4-yl 1-185 diMeCar diMeN (CH₂)₂ O 2-NO₂—Py-4-yl 1-186 diMeCar diMeN(CH₂)₂ O Thi-3-yl 1-187 diMeCar diMeN (CH₂)₂ O 2-MeOCO-Thi-3-yl 1-188diMeCar MeEtN (CH₂)₂ O 4-F—Ph 1-189 diMeCar MeEtN (CH₂)₂ O 4-NO₂—Ph1-190 diMeCar MeEtN (CH₂)₂ O 4-Cl—Ph 1-191 diMeCar MeEtN (CH₂)₂ O3-F-4-F—Ph 1-192 diMeCar MeHN (CH₂)₃ O 4-F—Ph 1-193 diMeCar MeHN (CH₂)₃O 4-Cl—Ph 1-194 diMeCar MeHN (CH₂)₃ O 4-NO₂—Ph 1-195 diMeCar MeHN (CH₂)₂O 2-F-4-NO₂—Ph 1-196 diMeCar diMeN (CH₂)₂ O 2-F-4-NO₂—Ph 1-197 diMeCarMeHN (CH₂)₂ S 2-F-4-NO₂—Ph 1-198 diMeCar diMeN (CH₂)₂ S 2-F-4-NO₂—Ph1-199 diMeCar MeHN (CH₂)₂ O 4-MeS—Ph 1-200 diMeCar diMeN (CH₂)₂ O4-MeS—Ph 1-201 diMeCar MeHN (CH₂)₂ S 4-MeS—Ph 1-202 diMeCar diMeN (CH₂)₂S 4-MeS—Ph 1-203 diMeCar MeHN (CH₂)₂ O pentaFPh 1-204 diMeCar diMeN(CH₂)₂ O pentaFPh 1-205 diMeCar MeHN (CH₂)₂ O naphtalene-1-yl 1-206diMeCar MeHN (CH₂)₂ O quinoline-6-yl 1-207 diMeCar MeHN (CH₂)₂ Onaphtalene-2-yl

TABLE 2 (Ib)

Com- pound No. R¹—(C═X¹) R²R³N A E Arom 2-1 diMeCar MeNH (CH₂)₂ — 4-F—Ph2-2 EtCar MeNH (CH₂)₂ O 4-F—Ph 2-3 EtCar MeNH (CH₂)₂ — 4-MeO—Ph 2-4 AcMeNH (CH₂)₂ O 4-F—Ph 2-5 tBu-(C═O) MeNH (CH₂)₂ O 4-F—Ph 2-6 diEtCar MeNH(CH₂)₂ O 4-F—Ph 2-7 diEtCar MeNH (CH₂)₂ — 4-Cl—Ph 2-8 diEtCar MeNH(CH₂)₂ — 3-Cl—Ph 2-9 diPrCar MeNH (CH₂)₂ O 4-F—Ph 2-10 MeEtCar MeNH(CH₂)₂ — 4-Cl—Ph 2-11 Mor-(C═O) MeNH (CH₂)₂ O 4-F—Ph 2-12 diMeTcr MeNH(CH₂)₂ O 4-F—Ph 2-13 diMeCar MeNH (CH₂)₂ — 4-Cl—Ph 2-14 diMeCar MeNu(CH₂)₂ — 4-CF₃—Ph 2-15 diMeCar MeNH (CH₂)₂ — 4-MeO—Ph 2-16 diMeCar diMeN(CH₂)₂ — 4-MeO—Ph 2-17 diMeCar MeNH (CH₂)₂ — 3-MeO-4-MeO—Ph 2-18 diMeCarMeNH (CH₂)₂ — 3,4-Mtdo-Ph 2-19 diMeCar MeNH (CH₂)₂ — 4-NO₂—Ph 2-20diMeCar MeNH (CH₂)₂ — 3-F-4-F—Ph 2-21 diMeCar diMeN (CH₂)₂ — 4-F—Ph 2-22diMeCar diMeN (CH₂)₂ — 4-Cl—Ph 2-23 diMeCar diMeN (CH₂)₂ — 4-NO₂—Ph 2-24diMeCar diMeN (CH₂)₂ — 3-F-4-F—Ph 2-25 diMeCar MeNH (CH₂)₃ — 4-F—Ph 2-26diMeCar MeNH (CH₂)₃ — 4-Cl—Ph 2-27 diMeCar MeNH (CH₂)₃ — 4-NO₂—Ph 2-28diMeCar MeNH (CH₂)₂ — 3-F-4-F—Ph 2-29 diMeCar diMeN (CH₂)₃ — 4-F—Ph 2-30diMeCar diMeN (CH₂)₃ — 4-Cl—Ph 2-31 diMeCar diMeN (CH₂)₃ — 4-NO₂—Ph 2-32diMeCar diMeN (CH₂)₃ — 3-F-4-F—Ph 2-33 diMeCar MeNH CH₂ O 4-F—Ph 2-34diMeCar MeNH CH₂ O 4-Cl—Ph 2-35 diMeCar MeNH CH₂ O 4-NO₂—Ph 2-36 diMeCarMeNH CH₂ O 3-F-4-F—Ph 2-37 diMeCar diMeN CH₂ O 4-F—Ph 2-38 diMeCar diMeNCH₂ O 4-Cl—Ph 2-39 diMeCar diMeN CH₂ O 4-NO₂—Ph 2-40 diMeCar diMeN CH₂ O3-F-4-F—Ph 2-41 diMeCar MeNH (CH₂)₂ S 4-F—Ph 2-42 diMeCar MeNH (CH₂)₂ S4-Cl—Ph 2-43 diMeCar MeNH (CH₂)₂ S 4-NO₂—Ph 2-44 diMeCar MeNH (CH₂)₂ S3-F-4-F—Ph 2-45 diMeCar diMeN (CH₂)₂ S 4-F—Ph 2-46 diMeCar diMeN (CH₂)₂S 4-Cl—Ph 2-47 diMeCar diMeN (CH₂)₂ S 4-NO₂—Ph 2-48 diMeCar diMeN (CH₂)₂S 3-F-4-F—Ph 2-49 diMeCar MeNH (CH₂)₂ NH 4-F—Ph 2-50 diMeCar MeNH (CH₂)₂NH 4-Cl—Ph 2-51 diMeCar MeNH (CH₂)₂ NH 3-F—Ph 2-52 diMeCar MeNH (CH₂)₂NH 3-Cl—Ph 2-53 diMeCar MeNH (CH₂)₂ NH 4-NO₂—Ph 2-54 diMeCar MeNH (CH₂)₂NH 3-F-4-F—Ph 2-55 diMeCar diMeN (CH₂)₂ NH 4-F—Ph 2-56 diMeCar diMeN(CH₂)₂ NH 4-Cl—Ph 2-57 diMeCar diMeN (CH₂)₂ NH 4-NO₂—Ph 2-58 diMeCardiMeN (CH₂)₂ NH 3-F-4-F—Ph 2-59 diMeCar MeNH (CH₂)₂ NAc 4-Cl—Ph 2-60diMeCar MeNH (CH₂)₂ NAc 3-F—Ph 2-61 diMeCar MeNH (CH₂)₂ NAc 4-NO₂—Ph2-62 diMeCar diMeN (CH₂)₂ NAc 4-Cl—Ph 2-63 diMeCar diMeN (CH₂)₂ NAc3-F—Ph 2-64 diMeCar diMeN (CH₂)₂ NAc 4-NO₂—Ph 2-65 diMeCar NH₂ (CH₂)₂ O4-F—Ph 2-66 diMeCar NH₂ (CH₂)₂ O 4-NO₂—Ph 2-67 diMeCar EtNH (CH₂)₂ O4-F—Ph 2-68 diMeCar EtNH (CH₂)₂ O 3-F—Ph 2-69 diMeCar EtNH (CH₂)₂ O4-Cl—Ph 2-70 diMeCar EtNH (CH₂)₂ O 3-NO₂—Ph 2-71 diMeCar EtNH (CH₂)₂ O4-NO₂—Ph 2-72 diMeCar EtNH (CH₂)₂ O 3-F-4-F—Ph 2-73 diMeCar PrNH (CH₂)₂O 4-F—Ph 2-74 diMeCar MeNH (CH₂)₂ O Ph 2-75 diMeCar MeNH (CH₂)₂ O 4-F—Ph2-76 diMeCar MeNH (CH₂)₂ O 3-F—Ph 2-77 diMeCar MeNH (CH₂)₂ O 2-F—Ph 2-78diMeCar MeNH (CH₂)₂ O 4-Cl—Ph 2-79 diMeCar MeNH (CH₂)₂ O 3-Cl—Ph 2-80diMeCar MeNH (CH₂)₂ O 2-Cl—Ph 2-81 diMeCar MeNH (CH₂)₂ O 4-Br—Ph 2-82diMeCar MeNH (CH₂)₂ O 4-Me—Ph 2-83 diMeCar MeNH (CH₂)₂ O 3-Me—Ph 2-84diMeCar MeNH (CH₂)₂ O 2-Me—Ph 2-85 diMeCar MeNH (CH₂)₂ O 4-CF₃—Ph 2-86diMeCar MeNH (CH₂)₂ O 4-MeO—Ph 2-87 diMeCar MeNH (CH₂)₂ O 3-MeO—Ph 2-88diMeCar MeNH (CH₂)₂ O 2-MeO—Ph 2-89 diMeCar MeNH (CH₂)₂ O 4-Ac—Ph 2-90diMeCar MeNH (CH₂)₂ O 3-Ac—Ph 2-91 diMeCar MeNH (CH₂)₂ O 4-CN—Ph 2-92diMeCar MeNH (CH₂)₂ O 4-NO₂—Ph 2-93 diMeCar MeNH (CH₂)₂ O 2-NO₂—Ph 2-94diMeCar MeNH (CH₂)₂ O 3-NO₂—Ph 2-95 diMeCar MeNH (CH₂)₂ O 4-NH₂—Ph 2-96diMeCar MeNH (CH₂)₂ O 3-NH₂—Ph 2-97 diMeCar MeNH (CH₂)₂ O 4-AcNM—Ph 2-98diMeCar MeNH (CH₂)₂ O 3-AcNM—Ph 2-99 diMeCar MeNH (CH₂)₂ O 4-COOH—Ph2-100 diMeCar MeNH (CH₂)₂ O 3,4-Mtdo-Ph 2-101 diMeCar MeNH (CH₂)₂ O2-F-4-F—Ph 2-102 diMeCar MeNH (CH₂)₂ O 3-F-4-F—Ph 2-103 diMeCar MeNH(CH₂)₂ O 3-F-5-F—Ph 2-104 diMeCar MeNH (CH₂)₂ O 3-F-4-Cl—Ph 2-105diMeCar MeNH (CH₂)₂ O 2-F-4-NO₂—Ph 2-106 diMeCar MeNH (CH₂)₂ O2-Cl-4-F—Ph 2-107 diMeCar MeNH (CH₂)₂ O 2-Cl-4-Cl—Ph 2-108 diMeCar MeNH(CH₂)₂ O 2-Cl-4-NO₂—Ph 2-109 diMeCar MeNH (CH₂)₂ O 3-Cl-4-F—Ph 2-110diMeCar MeNH (CH₂)₂ O 3-Cl-4-Cl—Ph 2-111 diMeCar MeNH (CH₂)₂ O2-Me-4-F—Ph 2-112 diMeCar MeNH (CH₂)₂ O 2-Me-4-Cl—Ph 2-113 diMeCar MeNH(CH₂)₂ O 3-Me-4-Cl—Ph 2-114 diMeCar MeNH (CH₂)₂ O 3-Me-4-Me—Ph 2-115diMeCar MeNH (CH₂)₂ O 3-Me-4-NO₂—Ph 2-116 diMeCar MeNH (CH₂)₂ O3-NO₂-4-Cl—Ph 2-117 diMeCar MeNH (CH₂)₂ O 3-F-4-F-5-F—Ph 2-118 diMeCarMeNH (CH₂)₂ O 2-F-3-F-5-F—Ph 2-119 diMeCar MeNH (CH₂)₂ O Py-3-yl 2-120diMeCar MeNH (CH₂)₂ O 5-Cl—Py-3-yl 2-121 diMeCar MeNH (CH₂)₂ O2-Me—Py-3-yl 2-122 diMeCar MeNH (CH₂)₂ O 6-Me—Py-3-yl 2-123 diMeCar MeNH(CH₂)₂ O Py-2-yl 2-124 diMeCar MeNH (CH₂)₂ O 6-Cl—Py-2-yl 2-125 diMeCarMeNH (CH₂)₂ O 6-CF₃—Py-2-yl 2-126 diMeCar MeNH (CH₂)₂ O 6-NO₂—Py-2-yl2-127 diMeCar MeNH (CH₂)₂ O Py-4-yl 2-128 diMeCar MeNH (CH₂)₂ O2-NO₂—Py-4-yl 2-129 diMeCar MeNH (CH₂)₂ O Thi-3-yl 2-130 diMeCar MeNH(CH₂)₂ O 2-MeOCO-Thi-3-yl 2-131 diMeCar diMeN (CH₂)₂ O Ph 2-132 diMeCardiMeN (CH₂)₂ O 4-F—Ph 2-133 diMeCar diMeN (CH₂)₂ O 3-F—Ph 2-134 diMeCardiMeN (CH₂)₂ O 2-F—Ph 2-135 diMeCar diMeN (CH₂)₂ O 4-Cl—Ph 2-136 diMeCardiMeN (CH₂)₂ O 3-Cl—Ph 2-137 diMeCar diMeN (CH₂)₂ O 2-Cl—Ph 2-138diMeCar diMeN (CH₂)₂ O 4-Br—Ph 2-139 diMeCar diMeN (CH₂)₂ O 4-Me—Ph2-140 diMeCar diMeN (CH₂)₂ O 3-Me—Ph 2-141 diMeCar diMeN (CH₂)₂ O2-Me—Ph 2-142 diMeCar diMeN (CH₂)₂ O 4-CF₃—Ph 2-143 diMeCar diMeN (CH₂)₂O 4-MeO—Ph 2-144 diMeCar diMeN (CH₂)₂ O 3-MeO—Ph 2-145 diMeCar diMeN(CH₂)₂ O 2-MeO—Ph 2-146 diMeCar diMeN (CH₂)₂ O 4-Ac—Ph 2-147 diMeCardiMeN (CH₂)₂ O 3-Ac—Ph 2-148 diMeCar diMeN (CH₂)₂ O 4-CN—Ph 2-149diMeCar diMeN (CH₂)₂ O 4-NO₂—Ph 2-150 diMeCar diMeN (CH₂)₂ O 2-NO₂—Ph2-151 diMeCar diMeN (CH₂)₂ O 3-NO₂—Ph 2-152 diMeCar diMeN (CH₂)₂ O4-NH₂—Ph 2-153 diMeCar diMeN (CH₂)₂ O 3-NH₂—Ph 2-154 diMeCar diMeN(CH₂)₂ O 4-AcNH—Ph 2-155 diMeCar diMeN (CH₂)₂ O 3-AcNH—Ph 2-156 diMeCardiMeN (CH₂)₂ O 4-COOH—Ph 2-157 diMeCar diMeN (CH₂)₂ O 3,4-Mtdo-Ph 2-158diMeCar diMeN (CH₂)₂ O 2-F-4-F—Ph 2-159 diMeCar diMeN (CH₂)₂ O3-F-4-F—Ph 2-160 diMeCar diMeN (CH₂)₂ O 3-F-5-F—Ph 2-161 diMeCar diMeN(CH₂)₂ O 3-F-4-Cl—Ph 2-162 diMeCar diMeN (CH₂)₂ O 2-F-4-NO₂—Ph 2-163diMeCar diMeN (CH₂)₂ O 2-Cl-4-F—Ph 2-164 diMeCar diMeN (CH₂)₂ O2-Cl-4-Cl—Ph 2-165 diMeCar diMeN (CH₂)₂ O 2-Cl-4-NO₂—Ph 2-166 diMeCardiMeN (CH₂)₂ O 3-Cl-4-F—Ph 2-167 diMeCar diMeN (CH₂)₂ O 3-Cl-4-Cl—Ph2-168 diMeCar diMeN (CH₂)₂ O 2-Me-4-F—Ph 2-169 diMeCar diMeN (CH₂)₂ O2-Me-4-Cl—Ph 2-170 diMeCar diMeN (CH₂)₂ O 3-Me-4-Cl—Ph 2-171 diMeCardiMeN (CH₂)₂ O 3-Me-4-Me—Ph 2-172 diMeCar diMeN (CH₂)₂ O 3-Me-4-NO₂—Ph2-173 diMeCar diMeN (CH₂)₂ O 3-NO₂-4-Cl—Ph 2-174 diMeCar diMeN (CH₂)₂ O3-F-4-F-5-F—Ph 2-175 diMeCar diMeN (CH₂)₂ O 2-F-3-F-5-F—Ph 2-176 diMeCardiMeN (CH₂)₂ O Py-3-yl 2-177 diMeCar diMeN (CH₂)₂ O 5-Cl—Py-3-yl 2-178diMeCar diMeN (CH₂)₂ O 2-Me—Py-3-yl 2-179 diMeCar diMeN (CH₂)₂ O6-Me—Py-3-yl 2-180 diMeCar diMeN (CH₂)₂ O Py-2-yl 2-181 diMeCar diMeN(CH₂)₂ O 6-Cl—Py-2-yl 2-182 diMeCar diMeN (CH₂)₂ O 6-CF₃—Py-2-yl 2-183diMeCar diMeN (CH₂)₂ O 6-NO₂—Py-2-yl 2-184 diMeCar diMeN (CH₂)₂ OPy-4-yl 2-185 diMeCar diMeN (CH₂)₂ O 2-NO₂—Py-4-yl 2-186 diMeCar diMeN(CH₂)₂ O Thi-3-yl 2-187 diMeCar diMeN (CH₂)₂ O 2-MeOCO-Thi-3-yl 2-188diMeCar MeEtN (CH₂)₂ O 4-F—Ph 2-189 diMeCar MeEtN (CH₂)₂ O 4-NO₂—Ph2-190 diMeCar MeEtN (CH₂)₂ O 4-Cl—Ph 2-191 diMeCar MeEtN (CH₂)₂ O3-F-4-F—Ph 2-192 diMeCar MeHN (CH₂)₃ O 4-F—Ph 2-193 diMeCar MeHN (CH₂)₃O 4-Cl—Ph 2-194 diMeCar MeHN (CH₂)₃ O 4-NO₂—Ph 2-195 diMeCar diMeN(CH₂)₂ O 2-F-4-NO₂—Ph 2-196 diMeCar diMeN (CH₂)₂ O 2-F-4-NO₂—Ph 2-197diMeCar MeHN (CH₂)₂ S 2-F-4-NO₂—Ph 2-198 diMeCar diMeN (CH₂)₂ S2-F-4-NO₂—Ph 2-199 diMeCar MeHN (CH₂)₂ O 4-MeS—Ph 2-200 diMeCar diMeN(CH₂)₂ O 4-MeS—Ph 2-201 diMeCar MeHN (CH₂)₂ S 4-MeS—Ph 2-202 diMeCardiMeN (CH₂)₂ S 4-MeS—Ph 2-203 diMeCar MeHN (CH₂)₂ O pentaFPh 2-204diMeCar diMeN (CH₂)₂ O pentaFPh 2-205 diMeCar MeHN (CH₂)₂ Onaphtalene-1-yl 2-206 diMeCar MeHN (CH₂)₂ O quinoline-6-yl 2-207 diMeCarMeHN (CH₂)₂ O naphtalene-2-yl

TABLE 3 (Ic)

Com- pound No. R¹—(C═X¹) R²R³N A E Arom 3-1 diMeCar NH₂ (CH₂)₂ O 4-F—Ph3-2 diMeCar NH₂ (CH₂)₂ O 4-NO₂—Ph 3-3 diMeCar EtNH (CH₂)₂ O 4-F—Ph 3-4diMeCar EtNH (CH₂)₂ O 3-F—Ph 3-5 diMeCar EtNH (CH₂)₂ O 4-Cl—Ph 3-6diMeCar EtNH (CH₂)₂ O 3-NO₂—Ph 3-7 diMeCar EtNH (CH₂)₂ O 4-NO₂—Ph 3-8diMeCar EtNH (CH₂)₂ O 3-F-4-F—Ph 3-9 diMeCar PrNH (CH₂)₂ O 4-F—Ph 3-10diMeCar MeNH (CH₂)₂ O Ph 3-11 diMeCar MeNH (CH₂)₂ O 4-F—Ph 3-12 diMeCarMeNH (CH₂)₂ O 3-F—Ph 3-13 diMeCar MeNH (CH₂)₂ O 2-F—Ph 3-14 diMeCar MeNH(CH₂)₂ O 4-Cl—Ph 3-15 diMeCar MeNH (CH₂)₂ O 3-Cl—Ph 3-16 diMeCar MeNH(CH₂)₂ O 2-Cl—Ph 3-17 diMeCar MeNH (CH₂)₂ O 4-Br—Ph 3-18 diMeCar MeNH(CH₂)₂ O 4-Me—Ph 3-19 diMeCar MeNH (CH₂)₂ O 3-Me—Ph 3-20 diMeCar MeNH(CH₂)₂ O 2-Me—Ph 3-21 diMeCar MeNH (CH₂)₂ O 4-CF₃—Ph 3-22 diMeCar MeNH(CH₂)₂ O 4-MeO—Ph 3-23 diMeCar MeNH (CH₂)₂ O 3-MeO—Ph 3-24 diMeCar MeNH(CH₂)₂ O 2-MeO—Ph 3-25 diMeCar MeNH (CH₂)₂ O 4-Ac—Ph 3-26 diMeCar MeNH(CH₂)₂ O 3-Ac—Ph 3-27 diMeCar MeNH (CH₂)₂ O 4-CN—Ph 3-28 diMeCar MeNH(CH₂)₂ O 4-NO₂—Ph 3-29 diMeCar MeNH (CH₂)₂ O 2-NO₂—Ph 3-30 diMeCar MeNH(CH₂)₂ O 3-NO₂—Ph 3-31 diMeCar MeNH (CH₂)₂ O 4-NH₂—Ph 3-32 diMeCar MeNH(CH₂)₂ O 3-NH₂—Ph 3-33 diMeCar MeNH (CH₂)₂ O 4-AcNH—Ph 3-34 diMeCar MeNH(CH₂)₂ O 3-AcNH—Ph 3-35 diMeCar MeNH (CH₂)₂ O 4-COOH—Ph 3-36 diMeCarMeNH (CH₂)₂ O 3,4-Mtdo-Ph 3-37 diMeCar MeNH (CH₂)₂ O 2-F-4-F—Ph 3-38diMeCar MeNH (CH₂)₂ O 3-F-4-F—Ph 3-39 diMeCar MeNH (CH₂)₂ O 3-F-5-F—Ph3-40 diMeCar MeNH (CH₂)₂ O 3-F-4-Cl—Ph 3-41 diMeCar MeNH (CH₂)₂ O2-F-4-NO₂—Ph 3-42 diMeCar MeNH (CH₂)₂ O 2-Cl-4-F—Ph 3-43 diMeCar MeNH(CH₂)₂ O 2-Cl-4-Cl—Ph 3-44 diMeCar MeNH (CH₂)₂ O 2-Cl-4-NO₂—Ph 3-45diMeCar MeNH (CH₂)₂ O 3-Cl-4-F—Ph 3-46 diMeCar MeNH (CH₂)₂ O3-Cl-4-Cl—Ph 3-47 diMeCar MeNH (CH₂)₂ O 2-Me-4-F—Ph 3-48 diMeCar MeNH(CH₂)₂ O 2-Me-4-Cl—Ph 3-49 diMeCar MeNH (CH₂)₂ O 3-Me-4-Cl—Ph 3-50diMeCar MeNH (CH₂)₂ O 3-Me-4-Me—Ph 3-51 diMeCar MeNH (CH₂)₂ O3-Me-4-NO₂—Ph 3-52 diMeCar MeNH (CH₂)₂ O 3-NO₂-4-Cl—Ph 3-53 diMeCar MeNH(CH₂)₂ O 3-F-4-F-5-F—Ph 3-54 diMeCar MeNH (CH₂)₂ O 2-F-3-F-5-F—Ph 3-55diMeCar MeNH (CH₂)₂ O Py-3-yl 3-56 diMeCar MeNH (CH₂)₂ O 5-Cl—Py-3-yl3-57 diMeCar MeNH (CH₂)₂ O 2-Me—Py-3-yl 3-58 diMeCar MeNH (CH₂)₂ O6-Me—Py-3-yl 3-59 diMeCar MeNH (CH₂)₂ O Py-2-yl 3-60 diMeCar MeNH (CH₂)₂O 6-Cl—Py-2-yl 3-61 diMeCar MeNH (CH₂)₂ O 6-CF₃—Py-2-yl 3-62 diMeCarMeNH (CH₂)₂ O 6-NO₂—Py-2-yl 3-63 diMeCar MeNH (CH₂)₂ O Py-4-yl 3-64diMeCar MeNH (CH₂)₂ O 2-NO₂—Py-4-yl 3-65 diMeCar MeNH (CH₂)₂ O Thi-3-yl3-66 diMeCar MeNH (CH₂)₂ O 2-MeOCO-Thi-3-yl 3-67 diMeCar diMeN (CH₂)₂ OPh 3-68 diMeCar diMeN (CH₂)₂ O 4-F—Ph 3-69 diMeCar diMeN (CH₂)₂ O 3-F—Ph3-70 diMeCar diMeN (CH₂)₂ O 2-F—Ph 3-71 diMeCar diMeN (CH₂)₂ O 4-Cl—Ph3-72 diMeCar diMeN (CH₂)₂ O 3-Cl—Ph 3-73 diMeCar diMeN (CH₂)₂ O 2-Cl—Ph3-74 diMeCar diMeN (CH₂)₂ O 4-Br—Ph 3-75 diMeCar diMeN (CH₂)₂ O 4-Me—Ph3-76 diMeCar diMeN (CH₂)₂ O 3-Me—Ph 3-77 diMeCar diMeN (CH₂)₂ O 2-Me—Ph3-78 diMeCar diMeN (CH₂)₂ O 4-CF₃—Ph 3-79 diMeCar diMeN (CH₂)₂ O4-MeO—Ph 3-80 diMeCar diMeN (CH₂)₂ O 3-MeO—Ph 3-81 diMeCar diMeN (CH₂)₂O 2-MeO—Ph 3-82 diMeCar diMeN (CH₂)₂ O 4-Ac—Ph 3-83 diMeCar diMeN (CH₂)₂O 3-Ac—Ph 3-84 diMeCar diMeN (CH₂)₂ O 4-CN—Ph 3-85 diMeCar diMeN (CH₂)₂O 4-NO₂—Ph 3-86 diMeCar diMeN (CH₂)₂ O 2-NO₂—Ph 3-87 diMeCar diMeN(CH₂)₂ O 3-NO₂—Ph 3-88 diMeCar diMeN (CH₂)₂ O 4-NH₂—Ph 3-89 diMeCardiMeN (CH₂)₂ O 3-NH₂—Ph 3-90 diMeCar diMeN (CH₂)₂ O 4-AcNH—Ph 3-91diMeCar diMeN (CH₂)₂ O 3-AcNH—Ph 3-92 diMeCar diMeN (CH₂)₂ O 4-COOH—Ph3-93 diMeCar diMeN (CH₂)₂ O 3,4-Mtdo-Ph 3-94 diMeCar diMeN (CH₂)₂ O2-F-4-F—Ph 3-95 diMeCar diMeN (CH₂)₂ O 3-F-4-F—Ph 3-96 diMeCar diMeN(CH₂)₂ O 3-F-5-F—Ph 3-97 diMeCar diMeN (CH₂)₂ O 3-F-4-Cl—Ph 3-98 diMeCardiMeN (CH₂)₂ O 2-F-4-NO₂—Ph 3-99 diMeCar diMeN (CH₂)₂ a 2-Cl-4-F—Ph3-100 diMeCar diMeN (CH₂)₂ a 2-Cl-4-Cl—Ph 3-101 diMeCar diMeN (CH₂)₂ O2-Cl-4-NO₂—Ph 3-102 diMeCar diMeN (CH₂)₂ O 3-Cl-4-F—Ph 3-103 diMeCardiMeN (CH₂)₂ O 3-Cl-4-Cl—Ph 3-104 diMeCar diMeN (CH₂)₂ O 2-Me-4-F—Ph3-105 diMeCar diMeN (CH₂)₂ O 2-Me-4-Cl—Ph 3-106 diMeCar diMeN (CH₂)₂ O3-Me-4-Cl—Ph 3-107 diMeCar diMeN (CH₂)₂ O 3-Me-4-Me—Ph 3-108 diMeCardiMeN (CH₂)₂ O 3-Me-4-NO₂—Ph 3-109 diMeCar diMeN (CH₂)₂ O 3-NO₂-4-Cl—Ph3-110 diMeCar diMeN (CH₂)₂ O 3-F-4-F-5-F—Ph 3-111 diMeCar diMeN (CH₂)₂ O2-F-3-F-5-F—Ph 3-112 diMeCar diMeN (CH₂)₂ O Py-3-yl 3-113 diMeCar diMeN(CH₂)₂ O 5-Cl—Py-3-yl 3-114 diMeCar diMeN (CH₂)₂ O 2-Me—Py-3-yl 3-115diMeCar diMeN (CH₂)₂ O 6-Me—Py-3-yl 3-116 diMeCar diMeN (CH₂)₂ O Py-2-yl3-117 diMeCar diMeN (CH₂)₂ O 6-Cl—Py-2-yl 3-118 diMeCar diMeN (CH₂)₂ O6-CF₃—Py-2-yl 3-119 diMeCar diMeN (CH₂)₂ O 6-NO₂—Py-2-yl 3-120 diMeCardiMeN (CH₂)₂ O Py-4-yl 3-121 diMeCar diMeN (CH₂)₂ O 2-NO₂—Py-4-yl 3-122diMeCar diMeN (CH₂)₂ O Thi-3-yl 3-123 diMeCar diMeN (CH₂)₂ O2-MeOCO-Thi-3-yl

TABLE 4 (Id)

Com- pound No. R^(a) R² R³ A E Arom 4-1 α-Me H Me (CH₂)₂ O 4-F—Ph 4-2α-Me H Me (CH₂)₂ O 4-NO₂—Ph 4-3 α-Me H Me (CH₂)₂ O 4-Cl—Ph 4-4 α-Me H Me(CH₂)₂ O 3-F—Ph 4-5 α-Me H Me (CH₂)₂ O 3-Cl—Ph 4-6 α-Me H Me (CH₂)₂ O4-SMe—Ph 4-7 α-Me H Me (CH₂)₂ O 2-Cl-3-Me—Ph 4-8 α-Me H Me (CH₂)₂ O2-Cl-4-NO₂—Ph 4-9 α-Me H Me (CH₂)₂ O 2-Cl-4-F—Ph 4-10 α-Me H Me (CH₂)₂ O3-Me-4-Cl—Ph 4-11 β-Me H Me (CH₂)₂ O 4-F—Ph 4-12 β-Me H Me (CH₂)₂ O4-NO₂—Ph 4-13 β-Me H Me (CH₂)₂ O 4-Cl—Ph 4-14 β-Me H Me (CH₂)₂ O 3-F—Ph4-15 β-Me H Me (CH₂)₂ O 3-Cl—Ph 4-16 β-Me H Me (CH₂)₂ O 4-SMe—Ph 4-17β-Me H Me (CH₂)₂ O 2-Cl-3-Me—Ph 4-18 β-Me H Me (CH₂)₂ O 2-Cl-4-NO₂—Ph4-19 β-Me H Me (CH₂)₂ O 2-Cl-4-F—Ph 4-20 β-Me H Me (CH₂)₂ O 3-Me-4-Cl—Ph4-21 α-(CH₂)— H (CH₂)₂ O 4-F—Ph 4-22 α-(CH₂)— H (CH₂)₂ O 4-NO₂—Ph 4-23α-(CH₂)— H (CH₂)₂ O 4-Cl—Ph 4-24 α-(CH₂)— H (CH₂)₂ O 3-F—Ph 4-25α-(CH₂)— H (CH₂)₂ O 3-Cl—Ph 4-26 α-(CH₂)— H (CH₂)₂ O 4-SMe—Ph 4-27α-(CH₂)— H (CH₂)₂ O 2-Cl-3-Me—Ph 4-28 α-(CH₂)— H (CH₂)₂ O 2-Cl-4-NO₂—Ph4-29 α-(CH₂)— H (CH₂)₂ O 2-Cl-4-F—Ph 4-30 α-(CH₂)— H (CH₂)₂ O3-Me-4-Cl—Ph 4-31 α-(CH₂)— Me (CH₂)₂ O 4-F—Ph 4-32 α-(CH₂)— Me (CH₂)₂ O4-NO₂—Ph 4-33 α-(CH₂)— Me (CH₂)₂ O 4-Cl—Ph 4-34 α-(CH₂)— Me (CH₂)₂ O3-F—Ph 4-35 α-(CH₂)— Me (CH₂)₂ O 3-Cl—Ph 4-36 α-(CH₂)— Me (CH₂)₂ O4-SMe—Ph 4-37 α-(CH₂)— Me (CH₂)₂ O 2-Cl-3-Me—Ph 4-38 α-(CH₂)— Me (CH₂)₂O 2-Cl-4-NO₂—Ph 4-39 α-(CH₂)— Me (CH₂)₂ O 2-Cl-4-F—Ph 4-40 α-(CH₂)— Me(CH₂)₂ O 3-Me-4-Cl—Ph 4-41 α-(CH₂)₂— H (CH₂)₂ O 4-F—Ph 4-42 α-(CH₂)₂— H(CH₂)₂ O 4-NO₂—Ph 4-43 α-(CH₂)₂— H (CH₂)₂ O 4-Cl—Ph 4-44 α-(CH₂)₂— H(CH₂)₂ O 3-F—Ph 4-45 α-(CH₂)₂— H (CH₂)₂ O 3-Cl—Ph 4-46 α-(CH₂)₂— H(CH₂)₂ O 4-SMe—Ph 4-47 α-(CH₂)₂— H (CH₂)₂ O 2-Cl-3-Me—Ph 4-48 α-(CH₂)₂—H (CH₂)₂ O 2-Cl-4-NO₂—Ph 4-49 α-(CH₂)₂— H (CH₂)₂ O 2-Cl-4-F—Ph 4-50α-(CH₂)₂— H (CH₂)₂ O 3-Me-4-Cl—Ph 4-51 α-(CH₂)₂— Me (CH₂)₂ O 4-F—Ph 4-52α-(CH₂)₂— Me (CH₂)₂ O 4-NO₂—Ph 4-53 α-(CH₂)₂— Me (CH₂)₂ O 4-Cl—Ph 4-54α-(CH₂)₂— Me (CH₂)₂ O 3-F—Ph 4-55 α-(CH₂)₂— Me (CH₂)₂ O 3-Cl—Ph 4-56α-(CH₂)₂— Me (CH₂)₂ O 4-SMe—Ph 4-57 α-(CH₂)₂— Me (CH₂)₂ O 2-Cl-3-Me—Ph4-58 α-(CH₂)₂— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 4-59 α-(CH₂)₂— Me (CH₂)₂ O2-Cl-4-F—Ph 4-60 α-(CH₂)₂— Me (CH₂)₂ O 3-Me-4-Cl—Ph 4-61 α-(CH₂)₂— Me(CH₂)₂ S 4-F—Ph 4-62 α-(CH₂)₂— Me (CH₂)₂ S 4-NO₂—Ph 4-63 α-(CH₂)₂— Me(CH₂)₂ S 4-Cl—Ph 4-64 α-(CH₂)₂— Me (CH₂)₂ S 3-F—Ph 4-65 α-(CH₂)₂— Me(CH₂)₂ S 3-Cl—Ph 4-66 α-(CH₂)₂— Me (CH₂)₂ S 4-SMe—Ph 4-67 α-(CH₂)₂— Me(CH₂)₂ S 2-Cl-3-Me—Ph 4-68 α-(CH₂)₂— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 4-69α-(CH₂)₂— Me (CH₂)₂ S 2-Cl-4-F—Ph 4-70 α-(CH₂)₂— Me (CH₂)₂ S3-Me-4-Cl—Ph 4-71 α-(CH₂)₂— Me (CH₂)₃ O 4-F—Ph 4-72 α-(CH₂)₂— Me (CH₂)₃O 4-NO₂—Ph 4-73 α-(CH₂)₂— Me (CH₂)₃ O 4-Cl—Ph 4-74 α-(CH₂)₂— Me (CH₂)₃ O3-F—Ph 4-75 α-(CH₂)₂— Me (CH₂)₃ O 3-Cl—Ph 4-76 α-(CH₂)₂— Me (CH₂)₃ O4-SMe—Ph 4-77 α-(CH₂)₂— Me (CH₂)₃ O 2-Cl-3-Me—Ph 4-78 α-(CH₂)₂— Me(CH₂)₃ O 2-Cl-4-NO₂—Ph 4-79 α-(CH₂)₂— Me (CH₂)₃ O 2-Cl-4-F—Ph 4-80α-(CH₂)₂— Me (CH₂)₃ O 3-Me-4-Cl—Ph 4-81 α-(CH₂)₃— H (CH₂)₂ O 4-F—Ph 4-82α-(CH₂)₃— H (CH₂)₂ O 4-NO₂—Ph 4-83 α-(CH₂)₃— H (CH₂)₂ O 4-Cl—Ph 4-84α-(CH₂)₃— H (CH₂)₂ O 3-F—Ph 4-85 α-(CH₂)₃— H (CH₂)₂ O 3-Cl—Ph 4-86α-(CH₂)₃— H (CH₂)₂ O 4-SMe—Ph 4-87 α-(CH₂)₃— H (CH₂)₂ O 2-Cl-3-Me—Ph4-88 α-(CH₂)₃— H (CH₂)₂ O 2-Cl-4-NO₂—Ph 4-89 α-(CH₂)₃— H (CH₂)₂ O2-Cl-4-F—Ph 4-90 α-(CH₂)₃— H (CH₂)₂ O 3-Me-4-Cl—Ph 4-91 α-(CH₂)₃— Me(CH₂)₂ O 4-F—Ph 4-92 α-(CH₂)₃— Me (CH₂)₂ O 4-NO₂—Ph 4-93 α-(CH₂)₃— Me(CH₂)₂ O 4-Cl—Ph 4-94 α-(CH₂)₃— Me (CH₂)₂ O 3-F—Ph 4-95 α-(CH₂)₃— Me(CH₂)₂ O 3-Cl—Ph 4-96 α-(CH₂)₃— Me (CH₂)₂ O 4-SMe—Ph 4-97 α-(CH₂)₃— Me(CH₂)₂ O 2-Cl-3-Me—Ph 4-98 α-(CH₂)₃— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 4-99α-(CH₂)₃— Me (CH₂)₂ O 2-Cl-4-F—Ph 4-100 α-(CH₂)₃— Me (CH₂)₂ O3-Me-4-Cl—Ph 4-101 α-(CH₂)₃— Me (CH₂)₂ S 4-F—Ph 4-102 α-(CH₂)₃— Me(CH₂)₂ S 4-NO₂—Ph 4-103 α-(CH₂)₃— Me (CH₂)₂ S 4-Cl—Ph 4-104 α-(CH₂)₃— Me(CH₂)₂ S 3-F—Ph 4-105 α-(CH₂)₃— Me (CH₂)₂ S 3-Cl—Ph 4-106 α-(CH₂)₃— Me(CH₂)₂ S 4-SMe—Ph 4-107 α-(CH₂)₃— Me (CH₂)₂ S 2-Cl-3-Me—Ph 4-108α-(CH₂)₃— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 4-109 α-(CH₂)₃— Me (CH₂)₂ S2-Cl-4-F—Ph 4-110 α-(CH₂)₃— Me (CH₂)₂ S 3-Me-4-Cl—Ph 4-111 α-(CH₂)₃— Me(CH₂)₃ O 4-F—Ph 4-112 α-(CH₂)₃— Me (CH₂)₃ O 4-NO₂—Ph 4-113 α-(CH₂)₃— Me(CH₂)₃ O 4-Cl—Ph 4-114 α-(CH₂)₃— Me (CH₂)₃ O 3-F—Ph 4-115 α-(CH₂)₃— Me(CH₂)₃ O 3-Cl—Ph 4-116 α-(CH₂)₃— Me (CH₂)₃ O 4-SMe—Ph 4-117 α-(CH₂)₃— Me(CH₂)₃ O 2-Cl-3-Me—Ph 4-118 α-(CH₂)₃— Me (CH₂)₃ O 2-Cl-4-NO₂—Ph 4-119α-(CH₂)₃— Me (CH₂)₃ O 2-Cl-4-F—Ph 4-120 α-(CH₂)₃— Me (CH₂)₂ O3-Me-4-Cl—Ph 4-121 α-CH═CH—CH₂— H (CH₂)₂ O 4-F—Ph 4-122 α-CH═CH—CH₂— H(CH₂)₂ O 4-NO₂—Ph 4-123 α-CH═CH—CH₂— H (CH₂)₂ O 4-Cl—Ph 4-124α-CH═CH—CH₂— H (CH₂)₂ O 3-F—Ph 4-125 α-CH═CH—CH₂— H (CH₂)₂ O 3-Cl—Ph4-126 α-CH═CH—CH₂— H (CH₂)₂ O 4-SMe—Ph 4-127 α-CH═CH—CH₂— H (CH₂)₂ O2-Cl-3-Me—Ph 4-128 α-CH═CH—CH₂— H (CH₂)₂ O 2-Cl-4-NO₂—Ph 4-129α-CH═CH—CH₂— H (CH₂)₂ O 2-Cl-4-F—Ph 4-130 α-CH═CH—CH₂— H (CH₂)₂ O3-Me-4-Cl—Ph 4-131 α-CH═CH—CH₂— Me (CH₂)₂ O 4-F—Ph 4-132 α-CH═CH—CH₂— Me(CH₂)₂ O 4-NO₂—Ph 4-133 α-CH═CH—CH₂— Me (CH₂)₂ O 4-Cl—Ph 4-134α-CH═CH—CH₂— Me (CH₂)₂ O 3-F—Ph 4-135 α-CH═CH—CH₂— Me (CH₂)₂ O 3-Cl—Ph4-136 α-CH═CH—CH₂— Me (CH₂)₂ O 4-SMe—Ph 4-137 α-CH═CH—CH₂— Me (CH₂)₂ O2-Cl-3-Me—Ph 4-138 α-CH═CH—CH₂— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 4-139α-CH═CH—CH₂— Me (CH₂)₂ O 2-Cl-4-F—Ph 4-140 α-CH═CH—CH₂— Me (CH₂)₂ O3-Me-4-Cl—Ph 4-141 α-CH═CH—CH₂— Me (CH₂)₂ S 4-F—Ph 4-142 α-CH═CH—CH₂— Me(CH₂)₂ S 4-NO₂—Ph 4-143 α-CH═CH—CH₂— Me (CH₂)₂ S 4-Cl—Ph 4-144α-CH═CH—CH₂— Me (CH₂)₂ S 3-F—Ph 4-145 α-CH═CH—CH₂— Me (CH₂)₂ S 3-Cl—Ph4-146 α-CH═CH—CH₂— Me (CH₂)₂ S 4-SMe—Ph 4-147 α-CH═CH—CH₂— Me (CH₂)₂ S2-Cl-3-Me—Ph 4-148 α-CH═CH—CH₂— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 4-149α-CH═CH—CH₂— Me (CH₂)₂ S 2-Cl-4-F—Ph 4-150 α-CH═CH—CH₂— Me (CH₂)₂ S3-Me-4-Cl—Ph 4-151 α-CH═CH—CH₂— Me (CH₂)₃ O 4-F—Ph 4-152 α-CH═CH—CH₂— Me(CH₂)₃ O 4-NO₂—Ph 4-153 α-CH═CH—CH₂— Me (CH₂)₃ O 4-Cl—Ph 4-154α-CH═CH—CH₂— Me (CH₂)₃ O 3-F—Ph 4-155 α-CH═CH—CH₂— Me (CH₂)₃ O 3-Cl—Ph4-156 α-CH═CH—CH₂— Me (CH₂)₃ O 4-SMe—Ph 4-157 α-CH═CH—CH₂— Me (CH₂)₃ O2-Cl-3-Me—Ph 4-158 α-CH═CH—CH₂— Me (CH₂)₃ O 2-Cl-4-NO₂—Ph 4-159α-CH═CH—CH₂— Me (CH₂)₃ O 2-Cl-4-F—Ph 4-160 α-CH═CH—CH₂— Me (CH₂)₃ O3-Me-4-Cl—Ph

TABLE 5 (Ie)

Com- pound No. R^(a) R² R³ A E Arom 5-1 α-Me H Me (CH₂)₂ O 4-F—Ph 5-2α-Me H Me (CH₂)₂ O 4-NO₂—Ph 5-3 α-Me H Me (CH₂)₂ O 4-Cl—Ph 5-4 α-Me H Me(CH₂)₂ O 3-F—Ph 5-5 α-Me H Me (CH₂)₂ O 3-Cl—Ph 5-6 α-Me H Me (CH₂)₂ O4-SMe—Ph 5-7 α-Me H Me (CH₂)₂ O 2-Cl-3-Me—Ph 5-8 α-Me H Me (CH₂)₂ O2-Cl-4-NO₂—Ph 5-9 α-Me H Me (CH₂)₂ O 2-Cl-4-F—Ph 5-10 α-Me H Me (CH₂)₂ O3-Me-4-Cl—Ph 5-11 β-Me H Me (CH₂)₂ O 4-F—Ph 5-12 β-Me H Me (CH₂)₂ O4-NO₂—Ph 5-13 β-Me H Me (CH₂)₂ O 4-Cl—Ph 5-14 β-Me H Me (CH₂)₂ O 3-F—Ph5-15 β-Me H Me (CH₂)₂ O 3-Cl—Ph 5-16 β-Me H Me (CH₂)₂ O 4-SMe—Ph 5-17β-Me H Me (CH₂)₂ O 2-Cl-3-Me—Ph 5-18 β-Me H Me (CH₂)₂ O 2-Cl-4-NO₂—Ph5-19 β-Me H Me (CH₂)₂ O 2-Cl-4-F—Ph 5-20 β-Me H Me (CH₂)₂ O 3-Me-4-Cl—Ph5-21 γ-Me H Me (CH₂)₂ O 4-F—Ph 5-22 γ-Me H Me (CH₂)₂ O 4-NO₂—Ph 5-23γ-Me H Me (CH₂)₂ O 4-Cl—Ph 5-24 γ-Me H Me (CH₂)₂ O 3-F—Ph 5-25 γ-Me H Me(CH₂)₂ O 3-Cl—Ph 5-26 γ-Me H Me (CH₂)₂ O 4-SMe—Ph 5-27 γ-Me H Me (CH₂)₂O 2-Cl-3-Me—Ph 5-28 γ-Me H Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-29 γ-Me H Me(CH₂)₂ O 2-Cl-4-F—Ph 5-30 γ-Me H Me (CH₂)₂ O 3-Me-4-Cl—Ph 5-31 δ-Me H Me(CH₂)₂ O 4-F—Ph 5-32 δ-Me H Me (CH₂)₂ O 4-NO₂—Ph 5-33 δ-Me H Me (CH₂)₂ O4-Cl—Ph 5-34 δ-Me H Me (CH₂)₂ O 3-F—Ph 5-35 δ-Me H Me (CH₂)₂ O 3-Cl—Ph5-36 δ-Me H Me (CH₂)₂ O 4-SMe—Ph 5-37 δ-Me H Me (CH₂)₂ O 2-Cl-3-Me—Ph5-38 δ-Me H Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-39 δ-Me H Me (CH₂)₂ O2-Cl-4-F—Ph 5-40 δ-Me H Me (CH₂)₂ O 3-Me-4-Cl—Ph 5-41 α-(CH₂)— H (CH₂)₂O 4-F—Ph 5-42 α-(CH₂)— H (CH₂)₂ O 4-NO₂—Ph 5-43 α-(CH₂)— H (CH₂)₂ O4-Cl—Ph 5-44 α-(CH₂)— H (CH₂)₂ O 3-F—Ph 5-45 α-(CH₂)— H (CH₂)₂ O 3-Cl—Ph5-46 α-(CH₂)— H (CH₂)₂ O 4-SMe—Ph 5-47 α-(CH₂)— H (CH₂)₂ O 2-Cl-3-Me—Ph5-48 α-(CH₂)— H (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-49 α-(CH₂)— H (CH₂)₂ O2-Cl-4-F—Ph 5-50 α-(CH₂)— H (CH₂)₂ O 3-Me-4-Cl—Ph 5-51 α-(CH₂)— Me(CH₂)₂ O 4-F—Ph 5-52 α-(CH₂)— Me (CH₂)₂ O 4-NO₂—Ph 5-53 α-(CH₂)— Me(CH₂)₂ O 4-Cl—Ph 5-54 α-(CH₂)— Me (CH₂)₂ O 3-F—Ph 5-55 α-(CH₂)— Me(CH₂)₂ O 3-Cl—Ph 5-56 α-(CH₂)— Me (CH₂)₂ O 4-SMe—Ph 5-57 α-(CH₂)— Me(CH₂)₂ O 2-Cl-3-Me—Ph 5-58 α-(CH₂)— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-59α-(CH₂)— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-60 α-(CH₂)— Me (CH₂)₂ O 3-Me-4-Cl—Ph5-61 α-(CH₂)₂— H (CH₂)₂ O 4-F—Ph 5-62 α-(CH₂)₂— H (CH₂)₂ O 4-NO₂—Ph 5-63α-(CH₂)₂— H (CH₂)₂ O 4-Cl—Ph 5-64 α-(CH₂)₂— H (CH₂)₂ O 3-F—Ph 5-65α-(CH₂)₂— H (CH₂)₂ O 3-Cl—Ph 5-66 α-(CH₂)₂— H (CH₂)₂ O 4-SMe—Ph 5-67α-(CH₂)₂— H (CH₂)₂ O 2-Cl-3-Me—Ph 5-68 α-(CH₂)₂— H (CH₂)₂ O2-Cl-4-NO₂—Ph 5-69 α-(CH₂)₂— H (CH₂)₂ O 2-Cl-4-F—Ph 5-70 α-(CH₂)₂— H(CH₂)₂ O 3-Me-4-Cl—Ph 5-71 α-(CH₂)₂— Me (CH₂)₂ O 4-F—Ph 5-72 α-(CH₂)₂—Me (CH₂)₂ O 4-NO₂—Ph 5-73 α-(CH₂)₂— Me (CH₂)₂ O 4-Cl—Ph 5-74 α-(CH₂)₂—Me (CH₂)₂ O 3-F—Ph 5-75 α-(CH₂)₂— Me (CH₂)₂ O 3-Cl—Ph 5-76 α-(CH₂)₂— Me(CH₂)₂ O 4-SMe—Ph 5-77 α-(CH₂)₂— Me (CH₂)₂ O 2-Cl-3-Me—Ph 5-78 α-(CH₂)₂—Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-79 α-(CH₂)₂— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-80α-(CH₂)₂— Me (CH₂)₂ O 3-Me-4-Cl—Ph 5-81 α-(CH₂)₂— Me (CH₂)₂ S 4-F—Ph5-82 α-(CH₂)₂— Me (CH₂)₂ S 4-NO₂—Ph 5-83 α-(CH₂)₂— Me (CH₂)₂ S 4-Cl—Ph5-84 α-(CH₂)₂— Me (CH₂)₂ S 3-F—Ph 5-85 α-(CH₂)₂— Me (CH₂)₂ S 3-Cl—Ph5-86 α-(CH₂)₂— Me (CH₂)₂ S 4-SMe—Ph 5-87 α-(CH₂)₂— Me (CH₂)₂ S2-Cl-3-Me—Ph 5-88 α-(CH₂)₂— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 5-89 α-(CH₂)₂— Me(CH₂)₂ S 2-Cl-4-F—Ph 5-90 α-(CH₂)₂— Me (CH₂)₂ S 3-Me-4-Cl—Ph 5-91α-(CH₂)₂— Me (CH₂)₃ O 4-F—Ph 5-92 α-(CH₂)₂— Me (CH₂)₃ O 4-NO₂—Ph 5-93α-(CH₂)₂— Me (CH₂)₃ O 4-Cl—Ph 5-94 α-(CH₂)₂— Me (CH₂)₃ O 3-F—Ph 5-95α-(CH₂)₂— Me (CH₂)₃ O 3-Cl—Ph 5-96 α-(CH₂)₂— Me (CH₂)₃ O 4-SMe—Ph 5-97α-(CH₂)₂— Me (CH₂)₃ O 2-Cl-3-Me—Ph 5-98 α-(CH₂)₂— Me (CH₂)₃ O2-Cl-4-NO₂—Ph 5-99 α-(CH₂)₂— Me (CH₂)₃ O 2-Cl-4-F—Ph 5-100 α-(CH₂)₂— Me(CH₂)₃ O 3-Me-4-Cl—Ph 5-101 α-(CH₂)₃— H (CH₂)₂ O 4-F—Ph 5-102 α-(CH₂)₃—H (CH₂)₂ O 4-NO₂—Ph 5-103 α-(CH₂)₃— H (CH₂)₂ O 4-Cl—Ph 5-104 α-(CH₂)₃— H(CH₂)₂ O 3-F—Ph 5-105 α-(CH₂)₃— H (CH₂)₂ O 3-Cl—Ph 5-106 α-(CH₂)₃— H(CH₂)₂ O 4-SMe—Ph 5-107 α-(CH₂)₃— H (CH₂)₂ O 2-Cl-3-Me—Ph 5-108α-(CH₂)₃— H (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-109 α-(CH₂)₃— H (CH₂)₂ O2-Cl-4-F—Ph 5-110 α-(CH₂)₃— H (CH₂)₂ O 3-Me-4-Cl—Ph 5-111 α-(CH₂)₃— Me(CH₂)₂ O 4-F—Ph 5-112 α-(CH₂)₃— Me (CH₂)₂ O 4-NO₂—Ph 5-113 α-(CH₂)₃— Me(CH₂)₂ O 4-Cl—Ph 5-114 α-(CH₂)₃— Me (CH₂)₂ O 3-F—Ph 5-115 α-(CH₂)₃— Me(CH₂)₂ O 3-Cl—Ph 5-116 α-(CH₂)₃— Me (CH₂)₂ O 4-SMe—Ph 5-117 α-(CH₂)₃— Me(CH₂)₂ O 2-Cl-3-Me—Ph 5-118 α-(CH₂)₃— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-119α-(CH₂)₃— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-120 α-(CH₂)₃— Me (CH₂)₂ O3-Me-4-Cl—Ph 5-121 α-(CH₂)₃— Me (CH₂)₂ S 4-F—Ph 5-122 α-(CH₂)₃— Me(CH₂)₂ S 4-NO₂—Ph 5-123 α-(CH₂)₃— Me (CH₂)₂ S 4-Cl—Ph 5-124 α-(CH₂)₃— Me(CH₂)₂ S 3-F—Ph 5-125 α-(CH₂)₃— Me (CH₂)₂ S 3-Cl—Ph 5-126 α-(CH₂)₃— Me(CH₂)₂ S 4-SMe—Ph 5-127 α-(CH₂)₃— Me (CH₂)₂ S 2-Cl-3-Me—Ph 5-128α-(CH₂)₃— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 5-129 α-(CH₂)₃— Me (CH₂)₂ S2-Cl-4-F—Ph 5-130 α-(CH₂)₃— Me (CH₂)₂ S 3-Me-4-Cl—Ph 5-131 α-(CH₂)₃— Me(CH₂)₃ O 4-F—Ph 5-132 α-(CH₂)₃— Me (CH₂)₃ O 4-NO₂—Ph 5-133 α-(CH₂)₃— Me(CH₂)₃ O 4-Cl—Ph 5-134 α-(CH₂)₃— Me (CH₂)₃ O 3-F—Ph 5-135 α-(CH₂)₃— Me(CH₂)₃ O 3-Cl—Ph 5-136 α-(CH₂)₃— Me (CH₂)₃ O 4-SMe—Ph 5-137 α-(CH₂)₃— Me(CH₂)₃ O 2-Cl-3-Me—Ph 5-138 α-(CH₂)₃— Me (CH₂)₃ O 2-Cl-4-NO₂—Ph 5-139α-(CH₂)₃— Me (CH₂)₃ O 2-Cl-4-F—Ph 5-140 α-(CH₂)₃— Me (CH₂)₃ O3-Me-4-Cl—Ph 5-141 α-CH═CH—CH₂— H (CH₂)₂ O 4-F—Ph 5-142 α-CH═CH—CH₂— H(CH₂)₂ O 4-NO₂—Ph 5-143 α-CH═CH—CH₂— H (CH₂)₂ O 4-Cl—Ph 5-144α-CH═CH—CH₂— H (CH₂)₂ O 3-F—Ph 5-145 α-CH═CH—CH₂— H (CH₂)₂ O 3-Cl—Ph5-146 α-CH═CH—CH₂— H (CH₂)₂ O 4-SMe—Ph 5-147 α-CH═CH—CH₂— H (CH₂)₂ O2-Cl-3-Me—Ph 5-148 α-CH═CH—CH₂— H (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-149α-CH═CH—CH₂— H (CH₂)₂ O 2-Cl-4-F—Ph 5-150 α-CH═CH—CH₂— H (CH₂)₂ O3-Me-4-Cl—Ph 5-151 α-CH═CH—CH₂— Me (CH₂)₂ O 4-F—Ph 5-152 α-CH═CH—CH₂— Me(CH₂)₂ O 4-NO₂—Ph 5-153 α-CH═CH—CH₂— Me (CH₂)₂ O 4-Cl—Ph 5-154α-CH═CH—CH₂— Me (CH₂)₂ O 3-F—Ph 5-155 α-CH═CH—CH₂— Me (CH₂)₂ O 3-Cl—Ph5-156 α-CH═CH—CH₂— Me (CH₂)₂ O 4-SMe—Ph 5-157 α-CH═CH—CH₂— Me (CH₂)₂ O2-Cl-3-Me—Ph 5-158 α-CH═CH—CH₂— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-159α-CH═CH—CH₂— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-160 α-CH═CH—CH₂— Me (CH₂)₂ O3-Me-4-Cl—Ph 5-161 α-CH═CH—CH₂— Me (CH₂)₂ S 4-F—Ph 5-162 α-CH═CH—CH₂— Me(CH₂)₂ S 4-NO₂—Ph 5-163 α-CH═CH—CH₂— Me (CH₂)₂ S 4-Cl—Ph 5-164α-CH═CH—CH₂— Me (CH₂)₂ S 3-F—Ph 5-165 α-CH═CH—CH₂— Me (CH₂)₂ S 3-Cl—Ph5-166 α-CH═CH—CH₂— Me (CH₂)₂ S 4-SMe—Ph 5-167 α-CH═CH—CH₂— Me (CH₂)₂ S2-Cl-3-Me—Ph 5-168 α-CH═CH—CH₂— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 5-169α-CH═CH—CH₂— Me (CH₂)₂ S 2-Cl-4-F—Ph 5-170 α-CH═CH—CH₂— Me (CH₂)₂ S3-Me-4-Cl—Ph 5-171 α-CH═CH—CH₂— Me (CH₂)₃ O 4-F—Ph 5-172 α-CH═CH—CH₂— Me(CH₂)₃ O 4-NO₂—Ph 5-173 α-CH═CH—CH₂— Me (CH₂)₃ O 4-Cl—Ph 5-174α-CH═CH—CH₂— Me (CH₂)₃ O 3-F—Ph 5-175 α-CH═CH—CH₂— Me (CH₂)₃ O 3-Cl—Ph5-176 α-CH═CH—CH₂— Me (CH₂)₃ O 4-SMe—Ph 5-177 α-CH═CH—CH₂— Me (CH₂)₃ O2-Cl-3-Me—Ph 5-178 α-CH═CH—CH₂— Me (CH₂)₃ O 2-Cl-4-NO₂—Ph 5-179α-CH═CH—CH₂— Me (CH₂)₃ O 2-Cl-4-F—Ph 5-180 α-CH═CH—CH₂— Me (CH₂)₃ O3-Me-4-Cl—Ph 5-181 δ-(CH₂)— H (CH₂)₂ O 4-F—Ph 5-182 δ-(CH₂)— H (CH₂)₂ O4-NO₂—Ph 5-183 δ-(CH₂)— H (CH₂)₂ O 4-Cl—Ph 5-184 δ-(CH₂)— H (CH₂)₂ O3-F—Ph 5-185 δ-(CH₂)— H (CH₂)₂ O 3-Cl—Ph 5-186 δ-(CH₂)— H (CH₂)₂ O4-SMe—Ph 5-187 δ-(CH₂)— H (CH₂)₂ O 2-Cl-3-Me—Ph 5-188 δ-(CH₂)— H (CH₂)₂O 2-Cl-4-NO₂—Ph 5-189 δ-(CH₂)— H (CH₂)₂ O 2-Cl-4-F—Ph 5-190 δ-(CH₂)— H(CH₂)₂ O 3-Me-4-Cl—Ph 5-191 δ-(CH₂)— Me (CH₂)₂ O 4-F—Ph 5-192 δ-(CH₂)—Me (CH₂)₂ O 4-NO₂—Ph 5-193 δ-(CH₂)— Me (CH₂)₂ O 4-Cl—Ph 5-194 δ-(CH₂)—Me (CH₂)₂ O 3-F—Ph 5-195 δ-(CH₂)— Me (CH₂)₂ O 3-Cl—Ph 5-196 δ-(CH₂)— Me(CH₂)₂ O 4-SMe—Ph 5-197 δ-(CH₂)— Me (CH₂)₂ O 2-Cl-3-Me—Ph 5-198 δ-(CH₂)—Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-199 δ-(CH₂)— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-200δ-(CH₂)— Me (CH₂)₂ O 3-Me-4-Cl—Ph 5-201 δ-(CH₂)₂— H (CH₂)₂ O 4-F—Ph5-202 δ-(CH₂)₂— H (CH₂)₂ O 4-NO₂—Ph 5-203 δ-(CH₂)₂— H (CH₂)₂ O 4-Cl—Ph5-204 δ-(CH₂)₂— H (CH₂)₂ O 3-F—Ph 5-205 δ-(CH₂)₂— H (CH₂)₂ O 3-Cl—Ph5-206 δ-(CH₂)₂— H (CH₂)₂ O 4-SMe—Ph 5-207 δ-(CH₂)₂— H (CH₂)₂ O2-Cl-3-Me—Ph 5-208 δ-(CH₂)₂— H (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-209 δ-(CH₂)₂— H(CH₂)₂ O 2-Cl-4-F—Ph 5-210 δ-(CH₂)₂— H (CH₂)₂ O 3-Me-4-Cl—Ph 5-211δ-(CH₂)₂— Me (CH₂)₂ O 4-F—Ph 5-212 δ-(CH₂)₂— Me (CH₂)₂ O 4-NO₂—Ph 5-213δ-(CH₂)₂— Me (CH₂)₂ O 4-Cl—Ph 5-214 δ-(CH₂)₂— Me (CH₂)₂ O 3-F—Ph 5-215δ-(CH₂)₂— Me (CH₂)₂ O 3-Cl—Ph 5-216 δ-(CH₂)₂— Me (CH₂)₂ O 4-SMe—Ph 5-217δ-(CH₂)₂— Me (CH₂)₂ O 2-Cl-3-Me—Ph 5-218 δ-(CH₂)₂— Me (CH₂)₂ O2-Cl-4-NO₂—Ph 5-219 δ-(CH₂)₂— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-220 δ-(CH₂)₂— Me(CH₂)₂ O 3-Me-4-Cl—Ph 5-221 δ-(CH₂)₂— Me (CH₂)₂ S 4-F—Ph 5-222 δ-(CH₂)₂—Me (CH₂)₂ S 4-NO₂—Ph 5-223 δ-(CH₂)₂— Me (CH₂)₂ S 4-Cl—Ph 5-224 δ-(CH₂)₂—Me (CH₂)₂ S 3-F—Ph 5-225 δ-(CH₂)₂— Me (CH₂)₂ S 3-Cl—Ph 5-226 δ-(CH₂)₂—Me (CH₂)₂ S 4-SMe—Ph 5-227 δ-(CH₂)₂— Me (CH₂)₂ S 2-Cl-3-Me—Ph 5-228δ-(CH₂)₂— Me (CH₂)₂ S 2-Cl-4-NO₂—Ph 5-229 δ-(CH₂)₂— Me (CH₂)₂ S2-Cl-4-F—Ph 5-230 δ-(CH₂)₂— Me (CH₂)₂ S 3-Me-4-Cl—Ph 5-231 δ-(CH₂)₂— Me(CH₂)₃ O 4-F—Ph 5-232 δ-(CH₂)₂— Me (CH₂)₃ O 4-NO₂—Ph 5-233 δ-(CH₂)₂— Me(CH₂)₃ O 4-Cl—Ph 5-234 δ-(CH₂)₂— Me (CH₂)₃ O 3-F—Ph 5-235 δ-(CH₂)₂— Me(CH₂)₃ O 3-Cl—Ph 5-236 δ-(CH₂)₂— Me (CH₂)₃ O 4-SMe—Ph 5-237 δ-(CH₂)₂— Me(CH₂)₃ O 2-Cl-3-Me—Ph 5-238 δ-(CH₂)₂— Me (CH₂)₃ O 2-Cl-4-NO₂—Ph 5-239δ-(CH₂)₂— Me (CH₂)₃ O 2-Cl-4-F—Ph 5-240 δ-(CH₂)₂— Me (CH₂)₃ O3-Me-4-Cl—Ph 5-241 δ-(CH₂)₃— H (CH₂)₂ O 4-F—Ph 5-242 δ-(CH₂)₃— H (CH₂)₂O 4-NO₂—Ph 5-243 δ-(CH₂)₃— H (CH₂)₂ O 4-Cl—Ph 5-244 δ-(CH₂)₃— H (CH₂)₂ O3-F—Ph 5-245 δ-(CH₂)₃— H (CH₂)₂ O 3-Cl—Ph 5-246 δ-(CH₂)₃— H (CH₂)₂ O4-SMe—Ph 5-247 δ-(CH₂)₃— H (CH₂)₂ O 2-Cl-3-Me—Ph 5-248 δ-(CH₂)₃— H(CH₂)₂ O 2-Cl-4-NO₂—Ph 5-249 δ-(CH₂)₃— H (CH₂)₂ O 2-Cl-4-F—Ph 5-250δ-(CH₂)₃— H (CH₂)₂ O 3-Me-4-Cl—Ph 5-251 δ-(CH₂)₃— Me (CH₂)₂ O 4-F—Ph5-252 δ-(CH₂)₃— Me (CH₂)₂ O 4-NO₂—Ph 5-253 δ-(CH₂)₃— Me (CH₂)₂ O 4-Cl—Ph5-254 δ-(CH₂)₃— Me (CH₂)₂ O 3-F—Ph 5-255 δ-(CH₂)₃— Me (CH₂)₂ O 3-Cl—Ph5-256 δ-(CH₂)₃— Me (CH₂)₂ O 4-SMe—Ph 5-257 δ-(CH₂)₃— Me (CH₂)₂ O2-Cl-3-Me—Ph 5-258 δ-(CH₂)₃— Me (CH₂)₂ O 2-Cl-4-NO₂—Ph 5-259 δ-(CH₂)₃—Me (CH₂)₂ O 2-Cl-4-F—Ph 5-260 δ-(CH₂)₃— Me (CH₂)₂ O 3-Me-4-Cl—Ph 5-261δ-(CH₂)₃— Me (CH₂)₂ S 4-F—Ph 5-262 δ-(CH₂)₃— Me (CH₂)₂ S 4-NO₂—Ph 5-263δ-(CH₂)₃— Me (CH₂)₂ S 4-Cl—Ph 5-264 δ-(CH₂)₃— Me (CH₂)₂ S 3-F—Ph 5-265δ-(CH₂)₃— Me (CH₂)₂ S 3-Cl—Ph 5-266 δ-(CH₂)₃— Me (CH₂)₂ S 4-SMe—Ph 5-267δ-(CH₂)₃— Me (CH₂)₂ S 2-Cl-3-Me—Ph 5-268 δ-(CH₂)₃— Me (CH₂)₂ S2-Cl-4-NO₂—Ph 5-269 δ-(CH₂)₃— Me (CH₂)₂ S 2-Cl-4-F—Ph 5-270 δ-(CH₂)₃— Me(CH₂)₂ S 3-Me-4-Cl—Ph 5-271 δ-(CH₂)₃— Me (CH₂)₃ O 4-F—Ph 5-272 δ-(CH₂)₃—Me (CH₂)₃ O 4-NO₂—Ph 5-273 δ-(CH₂)₃— Me (CH₂)₃ O 4-Cl—Ph 5-274 δ-(CH₂)₃—Me (CH₂)₃ O 3-F—Ph 5-275 δ-(CH₂)₃— Me (CH₂)₃ O 3-Cl—Ph 5-276 δ-(CH₂)₃—Me (CH₂)₃ O 4-SMe—Ph 5-277 δ-(CH₂)₃— Me (CH₂)₃ O 2-Cl-3-Me—Ph 5-278δ-(CH₂)₃— Me (CH₂)₃ O 2-Cl-4-NO₂—Ph 5-279 δ-(CH₂)₃— Me (CH₂)₃ O2-Cl-4-F—Ph 5-280 δ-(CH₂)₃— Me (CH₂)₃ O 3-Me-4-Cl—Ph 5-281 δ-CH═CH—CH₂—H (CH₂)₂ O 4-F—Ph 5-282 δ-CH═CH—CH₂— H (CH₂)₂ O 4-NO₂—Ph 5-283δ-CH═CH—CH₂— H (CH₂)₂ O 4-Cl—Ph 5-284 δ-CH═CH—CH₂— H (CH₂)₂ O 3-F—Ph5-285 δ-CH═CH—CH₂— H (CH₂)₂ O 3-Cl—Ph 5-286 δ-CH═CH—CH₂— H (CH₂)₂ O4-SMe—Ph 5-287 δ-CH═CH—CH₂— H (CH₂)₂ O 2-Cl-3-Me—Ph 5-288 δ-CH═CH—CH₂— H(CH₂)₂ O 2-Cl-4-NO₂—Ph 5-289 δ-CH═CH—CH₂— H (CH₂)₂ O 2-Cl-4-F—Ph 5-290δ-CH═CH—CH₂— H (CH₂)₂ O 3-Me-4-Cl—Ph 5-291 δ-CH═CH—CH₂— Me (CH₂)₂ O4-F—Ph 5-292 δ-CH═CH—CH₂— Me (CH₂)₂ O 4-NO₂—Ph 5-293 δ-CH═CH—CH₂— Me(CH₂)₂ O 4-Cl—Ph 5-294 δ-CH═CH—CH₂— Me (CH₂)₂ O 3-F—Ph 5-295δ-CH═CH—CH₂— Me (CH₂)₂ O 3-Cl—Ph 5-296 δ-CH═CH—CH₂— Me (CH₂)₂ O 4-SMe—Ph5-297 δ-CH═CH—CH₂— Me (CH₂)₂ O 2-Cl-3-Me—Ph 5-298 δ-CH═CH—CH₂— Me (CH₂)₂O 2-Cl-4-NO₂—Ph 5-299 δ-CH═CH—CH₂— Me (CH₂)₂ O 2-Cl-4-F—Ph 5-300δ-CH═CH—CH₂— Me (CH₂)₂ O 3-Me-4-Cl—Ph 5-301 δ-CH═CH—CH₂— Me (CH₂)₂ S4-F—Ph 5-302 δ-CH═CH—CH₂— Me (CH₂)₂ S 4-NO₂—Ph 5-303 δ-CH═CH—CH₂— Me(CH₂)₂ S 4-Cl—Ph 5-304 δ-CH═CH—CH₂— Me (CH₂)₂ S 3-F—Ph 5-305δ-CH═CH—CH₂— Me (CH₂)₂ S 3-Cl—Ph 5-306 δ-CH═CH—CH₂— Me (CH₂)₂ S 4-Sme-Ph5-307 δ-CH═CH—CH₂— Me (CH₂)₂ S 2-Cl-3-Me—Ph 5-308 δ-CH═CH—CH₂— Me (CH₂)₂S 2-Cl-4-NO₂—Ph 5-309 δ-CH═CH—CH₂— Me (CH₂)₂ S 2-Cl-4-F—Ph 5-310δ-CH═CH—CH₂— Me (CH₂)₂ S 3-Me-4-Cl—Ph 5-311 δ-CH═CH—CH₂— Me (CH₂)₃ O4-F—Ph 5-312 δ-CH═CH—CH₂— Me (CH₂)₃ O 4-NO₂—Ph 5-313 δ-CH═CH—CH₂— Me(CH₂)₃ O 4-Cl—Ph 5-314 δ-CH═CH—CH₂— Me (CH₂)₃ O 3-F—Ph 5-315δ-CH═CH—CH₂— Me (CH₂)₃ O 3-Cl—Ph 5-316 δ-CH═CH—CH₂— Me (CH₂)₃ O 4-Sme-Ph5-317 δ-CH═CH—CH₂— Me (CH₂)₃ O 2-Cl-3-Me—Ph 5-318 δ-CH═CH—CH₂— Me (CH₂)₃O 2-Cl-4-NO₂—Ph 5-319 δ-CH═CH—CH₂— Me (CH₂)₃ O 2-Cl-4-F—Ph 5-320δ-CH═CH—CH₂— Me (CH₂)₃ O 3-Me-4-Cl—Ph

Among the exemplary compounds, preferred are Compound No. 1-1, 1-7, 1-8,1-10, 1-13, 1-19, 1-23, 1-26, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39,1-40, 1-41, 1-42, 1-43, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52,1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-65, 1-66, 1-67,1-68, 1-70, 1-71, 1-72, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-81,1-82, 1-83, 1-84, 1-85, 1-86, 1-87, 1-88, 1-89, 1-90, 1-91, 1-92, 1-93,1-94, 1-95, 1-96, 1-97, 1-98, 1-99, 1-100, 1-101, 1-102, 1-103, 1-104,1-105, 1-106, 1-107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-113, 1-114,1-115, 1-116, 1-117,1-118, 1-119, 1-120, 1-121, 1-122, 1-123, 1-124,1-125, 1-126, 1-128, 1-129, 1-132, 1-133, 1-134, 1-135, 1-136, 1-137,1-138, 1-142, 1-143, 1-144, 1-145, 1-146, 1-148, 1-149, 1-150, 1-151,1-152, 1-153, 1-154, 1-155, 1-156, 1-157, 1-158, 1-160, 1-161, 1-162,1-163, 1-165, 1-174, 1-180, 1-181, 1-182, 1-183, 1-187, 1-188, 1-189,1-190, 1-191, 1-192, 1-193, 1-194, 1-195, 1-196, 1-199, 1-200, 1-203,1-204, 1-205, 1-206, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-9, 2-11, 2-12,2-13, 2-14, 2-15, 2-16, 2-17, 2-18, 2-19, 2-22,-2-24, 2-25, 2-26, 2-27,2-41, 2-42, 2-43, 2-49, 2-51, 2-53, 2-65, 2-67, 2-73, 2-75, 2-76, 2-77,2-78, 2-79, 2-80, 2-81, 2-82, 2-85, 2-86, 2-87, 2-88, 2-89, 2-90, 2-91,2-92, 2-93, 2-94, 2-95, 2-96, 2-97, 2-98, 2-100, 2-101, 2-102, 2-103,2-104, 2-105, 2-106, 2-107, 2-108, 2-109, 2-132, 2-133, 2-134, 2-135,2-136, 2-137, 2-138, 2-142, 2-143, 2-144, 2-145, 2-146, 2-147, 2-148,2-149, 2-150, 2-151, 2-152, 2-154, 2-155, 2-157, 2-158, 2-159, 2-160,2-161, 2-167, 2-173, 2-192, 2-193, 2-194, 2-199, 2-200, 3-11, 3-12,3-14, 3-15, 3-17, 3-21, 3-25, 3-26, 3-27, 3-28, 3-29, 3-30, 3-68, 3-69,3-71, 3-72, 3-74, 3-78, 3-82, 3-83, 3-84, 3-85, 3-87, 3-88, 3-89, 3-90,3-91, 4-2, 4-3, 4-6, 4-12, 4-13, 4-16, 4-52, 4-58, 4-60, 4-98, 4-132,4-136, 4-139, 4-140, 5-73, 5-160 and 5-300, more preferred are CompoundNo. 1-1, 1-7, 1-8, 1-10, 1-13, 1-19, 1-23, 1-26, 1-34, 1-39, 1-41, 1-42,1-43, 1-45, 1-46, 1-47, 1-49, 1-50, 1-51, 1-52, 1-53, 1-59, 1-60, 1-61,1-66, 1-67, 1-68, 1-70, 1-71, 1-72, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79,1-80, 1-81, 1-82, 1-84, 1-85, 1-86, 1-87, 1-88, 1-89, 1-90, 1-91, 1-92,1-93, 1-94, 1-95, 1-96, 1-97, 1-98, 1-99, 1-101, 1-102, 1-103, 1-104,1-105, 1-106, 1-107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-113, 1-114,1-115, 1-116, 1-117, 1-118, 1-119, 1-120, 1-121, 1-122, 1-123, 1-124,1-125, 1-126, 1-128, 1-129, 1-132, 1-133, 1-134, 1-135, 1-136, 1-137,1-142, 1-146, 1-149, 1-151, 1-156, 1-158, 1-159, 1-160, 1-165, 1-174,1-180, 1-181, 1-182, 1-183, 1-187, 1-188, 1-189, 1-190, 1-191, 1-192,1-193, 1-194, 1-195, 1-199, 1-200, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-9,2-11, 2-12, 2-13, 2-14, 2-15, 2-16, 2-17, 2-18, 2-22, 2-25, 2-26, 2-65,2-67, 2-73, 2-75, 2-78, 2-79, 2-82, 2-86, 2-88, 2-92, 2-94, 2-104,2-109, 2-132, 2-135, 2-136, 2-142, 2-149, 2-161, 2-167, 2-194, 2-199,2-200, 4-2, 4-12, 4-60, 4-132 and 4-139, further more preferred are thecompounds given below;

-   Compound No. 1-75: 4-[3-(4-fluorophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-76: 4-[3-(3-fluorophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-78: 4-[3-(4-chlorophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-79: 4-[3-(3-chlorophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-92: 4-[3-(4-nitrophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-102:    4-[3-(3,4-difluorophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-104:    4-[3-(4-chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-108:    4-[3-(2-chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-132:    4-[1-dimethylamino-3-(4-fluorophenoxy)propyl]phenyl    dimethylcarbamate-   Compound No. 1-133:    4-[1-dimethylamino-3-(3-fluorophenoxy)propyl]phenyl    dimethylcarbamate-   Compound No. 1-135:    4-[3-(4-chlorophenoxy)-1-dimethylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-136:    4-[3-(3-chlorophenoxy)-1-dimethylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-149:    4-[1-dimethylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate-   Compound No. 1-159:    4-[3-(3,4-difluorophenoxy)-1-dimethylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 1-165:    4-[3-(2-chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyl    dimethylcarbamate-   Compound No. 2-92: 3-[1-methylamino-3-(4-nitrophenoxy)propyl]phenyl    dimethylcarbamate-   Compound No. 2-149:    3-[1-dimethylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamate    and-   Compound No. 4-132:    2-methyl-1-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl    dimethylcarbamate    [Mode for Carrying out the Invention]

The compound (I) of the present invention can be obtained by Process Ato Process C described below.

In the above, R¹ to R³, R^(a), A, Arom, E, X¹ and X² have the samemeanings as defined above; R^(2a) has the same meaning as the above R²,or represents an allyl group or a protecting group for an amino group;R^(3a) has the same meaning as the above R³ or represents a protectinggroup for an amino group; R⁵ represents a hydrogen atom, a protectinggroup for a hydroxyl group or a group of the formula: R¹—C(═X¹)—(wherein R¹ and X¹ have the same meanings as defined above); R^(b) hasthe same meaning as the above R^(a), or represents a hydroxyl group, ahydroxyl group substituted by a leaving group or a vinyl group; Arom^(a)has the same meaning as the above Arom or represents a group in which acarboxyl group, a hydroxyl group or an amino group on Arom is protected,if necessary, by a protecting group for the respective functionalgroup(s); E^(a) represents an oxygen atom, a sulfur atom, an —NH— groupor an —NQ- group (wherein Q represents a protecting group for an aminogroup); E^(b) has the same meaning as the above E, except that it cannotrepresent a single bond; E^(c) represents a single bond, an oxygen atom,a sulfur atom, an —NH— group or an —NQ- group (wherein Q represents aprotecting group for an amino group); G represents a C₁-C₅ alkylenegroup; and L represents a hydroxyl group or a leaving group.

The protecting group for the hydroxyl group in R⁵ and Arom^(a) is notparticularly limited so long as it can stably protect the hydroxyl groupduring the reaction, and specifically means a protecting group which iscleavable by a chemical method such as hydrogenolysis, hydrolysis,electrolysis and photolysis, and may include the above “aliphatic acylgroup”; the above “aromatic acyl group”; the above “tetrahydropyranyl ortetrahydrothiopyranyl group”; the above “silyl group”; the above“alkoxymethyl group”; the above “substituted ethyl group”; the above“aralkyl group”; the above “alkoxycarbonyl group”; the above“alkenyloxycarbonyl group”; the above “aralkyloxycarbonyl group”.

The protecting group for the amino group in R^(2a), R^(3a), Arom^(a) andQ is not particularly limited so long as it can stably protect the aminogroup during the reaction, and specifically means a protecting groupwhich is cleavable by a chemical method such as hydrogenolysis,hydrolysis, electrolysis and photolysis, and may include the above“aliphatic acyl group”; the above “aromatic acyl group”; the above“alkoxycarbonyl group”; the above “aralkyloxycarbonyl group”; the above“silyl group”; the above “aralkyl group”; a “substituted methylenegroup” forming a Schiff base such as N,N-dimethylaminomethylene,benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene,5-chlorosalicylidene, diphenylmethylene or(5-chloro-2-hydroxyphenyl)phenylmethylene; an “aromatic sulfonyl group”such as an arylsulfonyl group, e.g., benzenesulfonyl, or an arylsulfonylgroup substituted by lower alkyl or lower alkoxy, e.g.,p-toluenesulfonyl, pentamethylbenzenesulfonyl, p-methoxybenzenesulfonyl,2,4,6-trimethoxybenzenesulfonyl or 3-methoxy-4-t-butylbenzenesulfonyl;or an “aliphatic sulfonyl group” such as an alkylsulfonyl group, e.g.,methanesulfonyl or t-butylsulfonyl, or an alkylsulfonyl groupsubstituted by a halogen atom, a silyl group or an aryl group, e.g.,trifluoromethylsulfonyl, trisilylethanesulfonyl or benzylsulfonyl.

The protecting group in Aroma is not particularly limited so long as itcan stably protect the carboxyl group during the reaction, andspecifically means a protecting group which is cleavable by a chemicalmethod such as hydrogenolysis, hydrolysis, electrolysis and photolysis,and may include the above “lower alkyl group”; the above “alkenylgroup”; the above “alkynyl group”; the above “lower alkyl group”; an“aliphatic acyl”—“lower alkyl group” such as acetylmethyl; the above“aralkyl group”; or the above “silyl group”.

The leaving group in R^(b) and L is not particularly limited so long asit is a functional group which can react with a nucleophilic reagent tocarry out a substitution reaction, and the group may include the above“halogen atom”; a “lower alkylsulfonyloxy group” such asmethanesulfonyloxy or ethanesulfonyloxy; a “halogen-substituted loweralkylsulfonyloxy group” such as trifluoromethanesulfonyloxy; an“aromatic sulfonyloxy group” such as an arylsulfonyloxy group, e.g.,benzenesulfonyloxy; a lower alkylated arylsulfonyloxy group, e.g.,p-toluenesulfonyloxy; or a halogen-substituted arylsulfonyloxy group,e.g., para-chlorobenzenesulfonyloxy.

In the following, the respective steps of Process A to Process C aredescribed in detail.

(Process A)

(Step A-1)

This step is to prepare a compound (IV) by reacting a compound (II)which is obtained by Process D, Process E, Process H, Process I orProcess J described later, or publicly known, or easily obtainable frompublicly known compounds, with a compound (III) which is publicly known,or easily obtainable from publicly known compounds, in the presence of abase.

This step is carried out by a reaction (reaction A-1a) in which thecompound (II) and the compound (III) form an ether in the case whereE^(a) is an oxygen or sulfur atom, or a reaction (reaction A-1b) inwhich the compound (II) and the compound (III) form an amine in the casewhere Ea is an amino group.

(Reaction A-1a)

This reaction is accomplished by <Method 1> in which after (α) an alkylor arylsulfonyl halide (preferably methanesulfonyl chloride) is reactedwith the hydroxyl group of the compound (III), (β) it is condensed withthe compound (II) in the presence of a base; or <Method 2> in which thecompound (III) and the compound (II) are condensed by a Mitsunobureaction described in Bull. Chem. Soc. Jap., 40, 2380 (1967).

<Method 1>

(α) Reaction of Hydroxyl Group and Sulfonyl Halide

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an aromatic hydrocarbon such asbenzene; or an ether such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, and is preferably an ether (particularlytetrahydrofuran).

The base to be employed here may be an organic base such astriethylamine, diisopropylamine, isopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline or N,N-diethylaniline, and is preferablytriethylamine.

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −20 to 50° C.,preferably from 0 to 25° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 5 minutes to10 hours, preferably from 10 minutes to 3 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture by conventional methods. Forexample, after the reaction, the desired compound is extracted by addingwater to the reaction mixture and adding a solvent immiscible with water(for example, benzene, ether, ethyl acetate, etc.), the extractedorganic layer is washed with water and is then dried using anhydrousmagnesium sulfate, etc. Thereafter, the solvent is evaporated to obtainthe desired compound. The thus obtained desired compound can be furtherpurified, if necessary, by conventional methods, for example,recrystallization, reprecipitation and chromatography. The desiredcompound of the present step can be used for the subsequent step withoutpurifying it.

(β) Condensation with the Compound (II)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting materials tosome extent, and may preferably be an-ether such as tetrahydrofuran,dioxane or dimethoxyethane; a nitrile such as acetonitrile orisobutyronitrile; an amide such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; or a sulfoxide suchas dimethyl sulfoxide or sulfolane, and is preferably an amide(particularly dimethylformamide).

The base to be empolyed here may be an alkali metal hydroxide such aslithium hydroxide, sodium hydroxide or potassium hydroxide; an alkalimetal hydride such as lithium hydride, sodium hydride or potassiumhydride; an alkyl lithium such as methyl lithium, ethyl lithium or butyllithium; or a lithium alkylamide such as lithium diisopropylamide,lithium dicyclohexylamide or lithium bis(trimethylsilyl)amide, and ispreferably a metal hydride (particularly sodium hydride).

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc. but it is usually from 0 to 180° C., preferablyfrom 0 to 50° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 1 to 24hours, preferably from 2 to 12 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture by conventional methods. Forexample, after completion of the reaction, the desired compound isextracted by adding water to the reaction mixture and adding a solventimmiscible with water (for example, benzene, ether, ethyl acetate,etc.), the extracted organic layer is washed with water and is driedusing anhydrous magnesium sulfate, etc. and thereafter the solvent isevaporated to obtain the desired compound. The thus obtained desiredcompound can be further purified, if necessary, by conventional methods,for example, recrystallization, reprecipitation and chromatography.

<Method 2>

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting materials tosome extent, and may be an aliphatic hydrocarbon such as hexane,heptane, ligroin or petroleum ether; an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; or an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, and is preferably an aliphatichydrocarbon, aromatic hydrocarbon or ether, more preferably an ether(particularly tetrahydrofuran).

The phosphine to be employed here may be a tri-C₁-C₆ alkylphosphine suchas trimethylphosphine, triethylphosphine, tripropylphosphine,tributylphosphine, tripentylphosphine or trihexylphosphine; a tri-C₆-C₁₀arylphosphine such as triphenylphosphine, triindenylphosphine ortrinaphthylphosphine; or a tri-C₆-C₁₀ arylphosphine which may have C₁-C₄alkyl as a-substituent group such as tolyldiphenylphosphine,tritolylphosphine, trimesitylphosphine, tributylphenylphosphine ortri-6-ethyl-2-naphthylphosphine, and is preferably a tri-C₁-C₆alkylphosphin (particularly trimethylphosphine, triethylphosphine,tripropylphosphine or tributylphosphine) or a tri-C₆-C₁₀ arylphosphine(particularly triphenylphosphine, triindenylphosphine ortrinaphthylphosphine), more preferably a tri-C₆-C₁₀ arylphosphine(particularly triphenylphosphine).

The azo compound to be employed here may be a di-C₁-C₄ alkylazodicarboxylate such as dimethyl azodicarboxylate, diethylazodicarboxylate, dipropyl azodicarboxylate or dibutyl azodicarboxylate,and is preferably diethyl azodicarboxylate.

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −10° C. to 100° C., preferablyfrom 0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 5 minutes to 24 hours,preferably from 10 minutes to 12 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by removing insolubles byfiltration in the case where they exist and evaporating the solvent. Theobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography.

(Reaction A-1b)

This reaction is carried out similarly to <Method 1> of the (ReactionA-1a).

(Step A-2)

This step is to prepare the compound (I), if necessary, by carrying outa deprotection reaction (Reaction A-2a) of a protecting group, anN-alkylation reaction (Reaction A-2b) of the amine, a carbamoylationreaction (Reaction A-2c) of the hydroxyl group and a cyclizationreaction (Reaction A-2d) on the compound (IV) obtained in step A-1.

(Reaction A-2a)

The removal of the protecting group of the amino group varies dependingon the kind thereof but it is generally carried out according to wellknown methods in the technology of synthetic organic chemistry asfollows.

In the case where the protecting group of the amino group is at-butoxycarbonyl group, a 2-trimethylsilylethoxycarbonyl group or ap-methoxybenzyloxycarbonyl group, it can-be eliminated by treating itwith an acid in an inert solvent or an aqueous solvent. At that time,the desired compound can be also obtained as a salt.

The acid to be employed here can be, for example, hydrochloric acid,sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroaceticacid, and is preferably hydrochloric acid, sulfuric acid, hydrobromicacid or trifluoroacetic acid.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting materials tosome extent, and may be an aliphatic hydrocarbon such as hexane,heptane, ligroin or petroleum ether; an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane,.dimethoxyethane ordiethylene glycol dimethyl ether; an ester such as methyl acetate orethyl acetate; an alcohol such as methanol, ethanol, propanol,isopropanol or butanol; an amide such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorictriamide; a sulfoxide such as dimethyl sulfoxide or sulfolane; analiphatic acid such as formic acid or acetic acid; or water or a mixtureof water and the above solvents, and is preferably a halogenatedhydrocarbon, ether, alcohol, aliphatic acid or a mixture of water andthe above solvents, more preferably an ester (particularly ethylacetate), or an ether (particularly tetrahydrofuran or dioxane).

The reaction temperature varies depending on the starting compound,solvent and acid used, but it is usually from −20° C. to 100° C.,preferably from 0° C. to 80° C.

The reaction time varies depending on the starting compound, solvent andacid used, but it is usually from 5 minutes to 20 hours, preferably fromone hour to 10 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by collecting the desiredcompound precipitated in the reaction solution or appropriatelyneutralizing the reaction solution, evaporating the solvent, pouringwater into the reaction mixture, adding a solvent immiscible with water(for example, benzene, ether, ethyl acetate, etc.) to perform anextraction and washing the organic layer containing the desired compoundwith water, followed by drying with anhydrous magnesium sulfate, etc.and evaporating off the solvent. The thus obtained desired compound canbe further purified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography.

In the case where the protecting group of the amino group is at-butoxycarbonyl group, it can also be eliminated by treating it with asilyl compound or Lewis acid, particularly in an inert solvent.

The silyl compound to be employed here is, for example, trimethylsilylchloride, trimethylsilyl iodide or trimethylsilyltrifluoromethanesulfonate, and the Lewis acid to be employed here is,for example, aluminum chloride.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may-be a halogenated hydrocarbon such asdichloromethane, chloroform or carbon tetrachloride; an ether such asdiethyl ether, tetrahydrofuran or dioxane; or a nitrile such asacetonitrile, and is preferably a halogenated hydrocarbon (particularlydichloromethane or chloroform) or a nitrile (particularly acetonitrile).

The reaction temperature varies depending on the starting compound,reagent and solvent, but it is usually from −20° to 100° C., preferablyfrom 0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent,solvent and reaction temperature, but it is usually from 10 minutes to10 hours, preferably from 30 minutes to 3 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by evaporating thesolvent, adding water to the reaction mixture and making the aqueouslayer alkaline to collect the precipitated substance by filtration, oradding a solvent immiscible with water (for example, benzene, ether,ethyl acetate, etc.) to perform an extraction and washing the organiclayer containing the desired compound with water, followed by dryingwith anhydrous magnesium sulfate, etc. and evaporating off the solvent.The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation and chromatography.

In the case where the protecting group of the amino group is anallyloxycarbonyl group, it can be usually eliminated by reacting it withtetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium chloride in the presence of from 1 to 3equivalents of potassium 2-ethylhexanoate, methyl malonate, dimedone ortributyl tin hydride in an inert solvent.

The solvent to be employed here is not particularly limited so long asit does not affect the present reaction, and may be a halogenatedhydrocarbon such as dichloromethane, chloroform or carbon tetrachloride;an ether such as diethyl ether, tetrahydrofuran or dioxane; or an estersuch as ethyl acetate or propyl acetate, and is preferably a halogenatedhydrocarbon (particularly dichloromethane), an ether (particularlytetrahydrofuran) or an ester (particularly ethyl acetate).

The reaction temperature varies depending on the starting compound,solvent and reducing agent used, but it is usually from −10° to 80° C.,preferably from 0° C. to 50° C.

The reaction time varies depending on the starting compound, solvent,reducing agent used, and the reaction temperature, but it is usuallyfrom 30 minutes to 24 hours, preferably from one hour to 8 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by removing the palladiumcatalyst by filtration and then evaporating the solvent, pouring waterinto the reaction mixture and making the aqueous layer alkaline tocollect the precipitated substance by filtration, or adding a solventimmiscible with water (for example, benzene, ether, ethyl acetate, etc.)to perform an extraction and washing the organic layer containing thedesired compound with water, followed by drying with anhydrous magnesiumsulfate, etc. and evaporating off the solvent. The obtained desiredcompound can be further purified, if necessary, by conventional methods,for example, recrystallization, reprecipitation or chromatography.

The removal of the protecting group of the hydroxyl group variesdepending on the kind thereof but it is generally carried out accordingto well known methods in the technology of synthetic organic chemistryas follows.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,cyclohexane, heptane, ligroin or petroleum ether; an aromatichydrocarbon such as benzene, toluene or xylene; an ether such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; an ester such as methyl acetate orethyl acetate; an alcohol such as methanol, ethanol, propanol,isopropanol, butanol or isobutanol; or a mixture obtained by arbitrarilymixing the above solvents and water, and is preferably an alcohol(particularly methanol) or a mixture of an alcohol and water.

The catalyst to be employed here is not particularly limited so long asit is usually used for catalytic reduction reactions, and may bepalladium black, palladium-carbon, palladium hydroxide, palladiumhydroxide-carbon, Raney nickel, rhodium-aluminum oxide, palladium-bariumsulfate, platinum oxide or platinum black, and is preferablypalladium-carbon or palladium hydroxide-carbon.

An acid can be added to effectively carry out the reaction in thepresent step. The acid to be employed here may be a mineral acid such ashydrochloric acid or hydrobromic acid; or an organic acid such as picricacid, formic acid, acetic acid, propionic acid, trifluoroacetic acid,benzenesulfonic acid, 4-toluenesulfonic acid or camphorsulfonic acid,and is preferably acetic acid.

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −10° to 100° C., preferably from0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 10 minutes to 48 hours,preferably from 30 minutes to 24 hours.

After the reaction, the desired compound is collected from the reactionmixture according to conventional methods. For example, after thereaction, the desired compound is obtained by removing the catalyst byfiltration and evaporating the filtrate. The obtained desired compoundcan be further purified, if necessary, by conventional methods, forexample, recrystallization, reprecipitation or chromatography.

The removal of the protecting group of the carboxyl group variesdepending on the kind thereof but it is generally carried out accordingto well known methods in the technology of synthetic organic chemistryas follows.

In the case where a lower alkyl group or an aryl group is used as theprotecting group of the carboxyl group, it can be removed by treatmentwith an acid or a base.

As the acid, hydrochloric acid, sulfuric acid, phosphoric acid orhydrobromic acid are used, and the base is not particularly limited solong as it does not affect other portions of the compound, and maypreferably be an alkali metal carbonate such as sodium carbonate orpotassium carbonate; an alkali metal hydroxide such as sodium hydroxideor potassium hydroxide; or a concentrated ammonia-methanol solution.

Isomerization sometimes occurs during hydrolysis by a base.

The solvent to be employed here is not particularly limited so long asit is usually used for hydrolysis reactions and does not inhibit thereaction, and may preferably be water; or a mixture of an organicsolvent such as an alcohol, e.g., methanol, ethanol and n-propanol or anether, e.g., tetrahydrofuran and dioxane, and water.

The reaction temperature and the reaction time vary depending on thestarting material, solvent, reagent used, etc. and are not particularlylimited, but the reaction is usually carried out at from 0° to 150° C.for from 1 to 10 hours.

In the case where the protecting group of the carboxyl group is adiaryl-substituted methyl group such as diphenylmethyl, it is usuallyeliminated by treating it with an acid in an inert solvent.

The solvent to be employed here is preferably an aromatic hydrocarbonsuch as anisole, and as the acid, a fluorinated organic acid such astrifluoroacetic acid is used.

The reaction temperature and the reaction time vary depending on thestarting material, solvent, acid used, etc., but the reaction is usuallycarried out at room temperature for 30 minutes to 10 hours.

In the case where the protecting group of the carboxyl group is anaralkyl group or a halogeno-lower alkyl group, it is usually eliminatedby reduction in a solvent.

As the reduction method, in the case where the protecting group of thecarboxyl group is a halogeno-lower alkyl group, a method employingchemical reduction such as zinc-acetic acid is preferably used, and inthe case where it is an aralkyl group, a method employing catalyticreduction using a catalyst such as palladium-carbon or platinum iscarried out, or a method employing chemical reduction using an alkalimetal sulfide such as potassium sulfide or sodium sulfide is carriedout.

The solvent to be employed here is not particularly limited so long asit does not affect the present reaction, and may preferably be analcohol such as methanol or ethanol; an ether such as tetrahydrofuran ordioxane; an aliphatic acid such as acetic acid; or a mixture of theseorganic solvents and water.

The reaction temperature and the reaction time vary depending on thestarting material, solvent and reduction method, but the reaction isusually carried out at from 0° C. to approximately room temperature forfrom 5 minutes to 12 hours.

In the case where the protecting group of the carboxyl group is analkoxymethyl group, it is usually eliminated by treating it with an acidin a solvent.

The acid to be employed here is not particularly limited so long as itis usually used as Bronsted acid, and may preferably be an inorganicacid such as hydrochloric acid or sulfuric acid, or an organic acid suchas acetic acid or para-toluenesulfonic acid.

The solvent to be employed here is not particularly limited so long asit does not affect the present reaction, and may preferably be analcohol such as methanol or ethanol; an ether such as tetrahydrofuran ordioxane; or a mixture of these organic solvents and water.

The reaction temperature and the reaction time vary depending on thestarting material, solvent and acid used, but the reaction is usuallycarried out at from 0° C. to 50° C. for from 10 minutes to 18 hours.

If the elimination of the protecting group of the carboxyl group iscarried out by treatment with ammonia according to conventional methods,the carboxyl group can be also amidated.

An alkali metal salt can be prepared, if desired, by dissolving the thusproduced carboxylic acid in a mixture of water and an organic solventimmiscible with water such as ethyl acetate, adding an aqueous solutionof an alkali metal carbonate or hydrogencarbonate such as aqueous sodiumhydrogencarbonate solution or aqueous potassium carbonate solution atfrom 0° C. to room temperature, followed by adjusting the pH of themixture to approximately 7 and collecting the precipitate by filtration.

The thus prepared salt or the above carboxylic acid can be reacted with2 equivalents of base (preferably an organic base such as triethylamineor dicyclohexylamine; an alkali metal salt hydride such as sodiumhydride; or an alkali metal carbonate or hydrogencarbonate such assodium hydrogencarbonate, sodium carbonate or potassium carbonate) in asolvent (preferably an ether such as tetrahydrofuran; or a polar solventsuch as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphorictriamide or triethylphosphate), followed by reaction with an aliphaticacyloxymethyl halide such as acetoxymethyl chloride orpropionyloxymethyl bromide, a 1-lower alkoxycarbonyloxyethyl halide suchas 1-methoxycarbonyloxyethyl chloride or 1-ethoxycarbonyloxyethyliodide, a phthalidyl halide, or a(2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl halide, to prepare an esterproduct protected by-a protecting group of the carboxyl group which iseasily hydrolized in a living body.

The reaction temperature and the reaction time vary depending on thestarting material, solvent and the kind of reaction reagent, but thereaction is usually carried out at from 0° C. to 100° C. for from 0.5 to10 hours.

(Reaction A-2b)

The N-alkylation of the amine is accomplished by <Method 1>: acombination of an alkylcarbonyl compound and a reducing agent or <Method2>: reaction with an alkyl halide in the presence of a base.

<Method 1>

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be water; a halogenated hydrocarbon such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; an amide such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone orhexamethylphosphoric triamide; a sulfoxide such as dimethyl sulfoxide orsulfolane; or an organic base such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine dicyclohexylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,quinoline, N,N-dimethylaniline or N,N-diethylaniline; and is preferablyan alcohol. The reaction can be also carried out, if necessary, withoutusing a solvent.

The reducing agent to be employed here may be a metal borohydride suchas sodium borohydride or sodium cyanoborohydride; a combination ofhydrogen gas and a catalyst such as palladium-carbon, platinum or Raneynickel; or a combination of zinc and hydrochloric acid, and ispreferably a metal borohydride. In the case where the alkylating agentis formaldehyde, formic acid can be also used.

The reaction temperature varies depending on the starting compound,reagent and solvent, but it is usually from −20° C. to 200° C.,preferably from 0° C. to 100° C.

The reaction time varies depending mainly on the reaction temperature,starting compound, and the kind of solvent used, but it is usually from10 minutes to 24 hours, preferably from one hour to 12 hours.

After the reaction, the desired compound of the present reaction isobtained, for example, by concentrating the reaction mixture, adding anorganic solvent immiscible with water such as ethyl acetate, washingwith water, separating the organic layer containing the desiredcompound, drying with anhydrous magnesium sulfate and evaporating thesolvent.

<Method 2>

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,heptane, ligroin or petroleum ether; an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; an amide such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidone orhexamethylphosphoric triamide; a sulfoxide such as dimethyl sulfoxide orsulfolane; or an organic base such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, *diisopropylethylamine,dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine,picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline orN,N-diethylaniline, and is preferably an amide, particularly preferablyN,N-dimethylacetamide.

The base to be employed here may be an alkali metal carbonate such assodium carbonate, potassium carbonate or lithium carbonate; an alkalimetal hydrogencarbonate such as sodium hydrogencarbonate, potassiumhydrogencarbonate or lithium hydrogencarbonate; or an organic base suchas N-methylmorpholine, triethylamine, tripropylamine, tributylamine,diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine,4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably an alkalimetal carbonate, particularly preferably potassium carbonate.

Sodium iodide may be also added in order to effectively carry out thereaction.

The reaction temperature varies depending on the starting compound,reagent and solvent, but it is usually from 0° C. to 200° C., preferablyfrom 20° C. to 100° C.

The reaction time varies mainly depending on the reaction temperature,starting compound, and the kind of solvent used, but it is usually from10 minutes to 24 hours, preferably from one hour to 12 hours.

After the reaction, the desired compound of the present reaction isobtained, for example, by concentrating the reaction mixture, adding anorganic solvent immiscible with water such as ethyl acetate, washingwith water, separating the organic layer containing the desiredcompound, drying with anhydrous magnesium sulfate and evaporating thesolvent.

(Reaction A-2c)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane orheptane; an aromatic hydrocarbon such as benzene, toluene or xylene; ahalogenated hydrocarbon such as dichloromethane, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; anester such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; or an amide such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone orhexamethylphosphoric triamide, and is preferably a halogenatedhydrocarbon (particularly dichloromethane), an ether (particularlytetrahydrofuran) or an amide (particularly N,N-dimethylformamide).

The base to be employed here may be an alkali metal carbonate such assodium carbonate, potassium carbonate or lithium carbonate; an alkalimetal hydride such as lithium hydride, sodium hydride or potassiumhydride; or an organic amine such as triethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-S-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)or 1,8-diazabicyclo[5.4.0)undec-7-ene (DBU), and is preferably an alkalimetal carbonate (particularly potassium carbonate) or an organic amine(particularly triethylamine).

The reaction temperature varies depending on the starting compound,solvent and base used, but it is usually from −20° C. to 100° C.,preferably from 0° C. to 50° C.

The reaction time varies depending on the starting compound, solvent andbase used, but it is usually from 5 minutes to 48 hours, preferably fromone hour to 10 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound precipitated in the reaction solutionis obtained by collecting through filtration, or appropriatelyneutralizing the reaction solution, evaporating the solvent, pouringwater into the reaction mixture and adding a solvent immiscible withwater (for example, benzene, ether, ethyl acetate, etc.) to perform anextraction, washing the organic layer containing the desired compoundwith water, drying with anhydrous magnesium sulfate and-evaporating thesolvent. The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation or chromatography.

(Reaction A-2d)

This reaction is accomplished by vinylating the phenyl group (α) andallylating the amino group (i), followed by cyclization of the vinylgroup and the allyl group by olefin metathesis (γ). Either thevinylation (α) or the allylation (β) may be carried out first.

(α)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane orheptane; an aromatic hydrocarbon such as benzene, toluene or xylene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a nitrilesuch as acetonitrile or isobutyronitrile; or an amide such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,N-methylpyrrolidinone or hexamethylphosphoric triamide, and ispreferably an ether (particularly tetrahydrofuran or dioxane) or anamide (particularly N,N-dimethylformamide).

Lithium chloride can be added for the purpose of promoting the reaction.

The catalyst to be employed here is not particularly limited so long asit can vinylate the hydroxyl group of the phenol, and is preferably apalladium catalyst, that is, a catalyst containing 0 valent- or 2valent-palladium metal which is used in organic synthesis, and may bepalladium metal, palladium-carbon, palladium hydroxide, palladiumchloride, palladium (II) acetate,tris(dibenzylideneacetone)dipalladium-chloroform, allyl palladiumchloride, [1,2-bis(diphenylphosphino)ethane]palladium dichloride,bis(tri-o-toluylphosphine)palladium dichloride,bis(triphenylphosphine)palladium dichloride,tetrakis(triphenylphosphine)palladium,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, or a catalystproduced in solution by adding a ligand into the reaction solution ofthese. The ligand added into the reaction solution may be a phosphoricligand such as 1,1′-bis(diphenylphosphino)ferrocene,bis(2-diphenylphosphinophenyl)ether, 2,2′-bis(diphenylphosphino)-1,1′-binaphthol, 1,3-bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, tri-o-toluylphosphine,2-diphenylphosphino-2′-methoxy-1,1′-binaphthyl or2,2-bis(diphenylphosphino)-1,1′-binaphthyl. The above palladium catalystis preferably palladium acetate,tris(dibenzylideneacetone)dipalladium-chloroform, a combination ofpalladium acetate and the ligand bis(2-diphenylphosphinophenyl)ether, ora combination of tris(dibenzylideneacetone)dipalladium-chloroform andthe ligand 1,1′-bis(diphenylphosphino)ferrocene, more preferably acombination of palladium acetate and the ligandbis(2-diphenylphosphinophenyl)ether, or a combination oftris(dibenzylideneacetone)dipalladium-chloroform and the ligand1,1′-bis(diphenylphosphino)ferrocene.

The reagent to be employed in the present reaction is not particularlylimited so long as it is used for Stille coupling and produces a vinylgroup, and is preferably tributylvinyl tin.

The reaction temperature varies depending on the starting compound,solvent and base used, but it is usually from −20° C. to 50° C.,preferably from 0° C. to 25° C.

The reaction time varies depending on the starting compound, solvent andbase used, but it is usually from 5 minutes to 24 hours, preferably from30 minutes to 12 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by collecting the desiredcompound precipitated in the reaction solution by filtration, or addinga saturated aqueous potassium fluoride solution, filtering the solventto evaporate the solvent in the filtrate, adding water and a solventimmiscible with water (for example, benzene, ether, ethyl acetate, etc.)to perform an extraction, washing the organic layer containing thedesired compound with water, drying with anhydrous magnesium sulfate andevaporating the solvent. The obtained desired compound can be furtherpurified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography.

(β)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane orheptane; an aromatic hydrocarbon such as benzene, toluene or xylene; anether such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane or diethylene glycol dimethyl ether; a nitrilesuch as acetonitrile or isobutyronitrile; or an amide such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,N-methylpyrrolidinone or hexamethylphosphoric triamide, and ispreferably an amide (particularly N,N-dimethylformamide).

The allylating reagent to be employed here is on allyl halide,preferably allyl bromide or allyl iodide, more preferably allyl bromide.

The base to be employed here may be an alkali metal carbonate such assodium carbonate, potassium carbonate or lithium carbonate; an alkalimetal hydride such as lithium hydride, sodium hydride or potassiumhydride; an alkali metal alkoxide such as sodium methoxide, sodiumethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxideor lithium methoxide; or an organic base such as N-methylmorpholine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine,dicyclohexylamine, N-methylpiperidine; pyridine, 4-pyrrolidinopyridine,picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably an alkalimetal hydride (particularly sodium hydride).

The reaction temperature varies depending on the starting compound,solvent and base used, but it is usually from 0° C. to 200° C.,preferably from 20° C. to 100° C.

The reaction time varies depending on the starting compound, solvent andbase used, but it is usually from 5 minutes to 48 hours, preferably from1 hour to 12 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by collecting the desiredcompound precipitated in the reaction solution, or neutralizingappropriately the reaction mixture, pouring water into the reactionmixture, adding a solvent immiscible with water (for example, benzene,ether, ethyl acetate, etc.) to perform an extraction, washing theorganic layer containing the desired compound with water, followed bydrying with anhydrous magnesium sulfate, and evaporating the solvent.The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation or chromatography.

(γ)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material-tosome extent, and may be an aromatic hydrocarbon such as benzene, tolueneor xylene; a halogenated hydrocarbon such as dichloromethane,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene ordichlorobenzene; or an ether such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, and is preferably an aromatic hydrocarbon or a halogenatedhydrocarbon, more preferably toluene or dichloromethane.

The catalyst to be employed here is not particularly limited so long asit can be used for olefin metathesis, and is preferably Grubbs catalystin which two phosphine ligands are coordinated to benzylidenedihalogenated ruthenium, and this catalyst may bebenzylidenebis(tricyclohexylphosphine)dichlororuthenium,benzylidenebis(triphenylphosphine)dichlororuthenium, orbenzylidenedichloro(1,3-dimesityl-2-imidazolidinylidene)(tricyclohexylphosphine)ruthenium.

The reaction temperature varies depending on the starting compound,solvent and base used, but it is usually from 0° C. to 120° C.,preferably from 25° C. to 40° C.

The reaction time varies depending on the starting compound, solvent andbase used, but it is usually from 1 hour to 24 hours, preferably from 2hours to 12 hours.

After completion of the reaction, the desired compound of the presentreaction is collected from the reaction mixture according toconventional methods. For example, the desired compound is obtained bycollecting the desired compound precipitated in the reaction solution,or evaporating the solvent. The thus obtained desired compound can befurther purified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography.

In the present step, any of the deprotection reactions of the protectinggroups, the N-alkylation reaction of the amine, the carbonylationreaction of the hydroxyl group, and the cyclization reaction, may becarried out first depending on the structure of the desired compound. Inthe case where the conditions are common to them, the reactions may becarried out consecutively without purification.

(Process B)

(Step B-1)

This step is to prepare a compound (V) by oxidizing the hydroxyl groupof the compound (IIa) obtained by Process D, Process E, Process H,Process I or Process J described later, or which is publicly known oreasily obtainable from known compounds, to a formyl group (ReactionB-1a), carrying out a Wittig reaction on the formyl group (ReactionB-1b), and reducing the obtained compound (Reaction B-1c).

(Reaction B-1a)

The oxidizing agent to be employed here is not particularly limited solong as it is usually used for oxidation reactions and may preferably bea manganese oxide such as manganese dioxide; a chromic acid compoundsuch as chromic anhydride-pyridine complex; a reagent used for Swernoxidation (a combination of dimethyl sulfoxide and an activating agent(dicyclohexylcarbodiimide, dicyclohexylcarbodiimide andpyridine-trifluoroacetic acid, oxalyl chloride, acetic anhydride,phosphorus pentoxide, pyridine-sulfuric anhydride, sulfurtrioxide-pyridine, mercury acetate, chlorine or N-chlorosuccinimide)); atransition metal oxidizing agent such as tetrapropylammoniumperruthenate; or a high valence iodine oxidizing agent such as1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, and is morepreferably a chromic acid compound.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such asdichloromethane, chloroform or dichloroethane; an ester such as ethylacetate; an ether such as tetrahydrofuran, dioxane or dimethoxyethane; aketone such as acetone or methyl ethyl ketone; or a nitrile such asacetonitrile or isobutyronitrile, and is more preferably a halogenatedhydrocarbon (particularly dichloromethane).

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −60° C. to 50° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc. but it is usually from one to 16hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by appropriatelyneutralizing the reaction mixture, or in the case where insolublesexist, removing them by filtration, adding an organic solvent immisciblewith water such as ethyl acetate, washing with water, separating theorganic layer containing the desired compound, drying with anhydrousmagnesium sulfate and evaporating the solvent. The thus obtained desiredcompound can be further purified, if necessary, by conventional methods,for example, recrystallization, reprecipitation or chromatography.

(Reaction B-1b)

The reaction is carried out in the presence of a base. The base to beemployed here may be an alkyl lithium such as methyl lithium or butyllithium; an alkali metal hydride such as sodium hydride or potassiumhydride; an alkali metal amide such as lithium amide, sodium amide orpotassium amide; an alkali metal alkoxide such as sodium methoxide,sodium ethoxide, potassium propoxide, sodium butoxide,potassium-t-butoxide or sodium-t-pentoxide; or an alkali metaldisilazide such as lithium hexamethyldisilazide, sodiumhexamethyldisilazide or potassium hexamethyldisiliazide; and ispreferably an alkali metal hydride, alkali metal alkoxide or alkalimetal disilazide, more preferably sodium hydride, potassium hydride,potassium-t-butoxide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide or lithium hexamethyldisilazide, particularlypreferably sodium hydride or potassium hydride.

The Wittig reagent to be employed here is preferably a combination of atriphenylphosphorane such as benzylidenetriphenylphosphorane, and thecorresponding benzyl halide compound, or a phosphonium salt obtained bythe combination.

The solvent to be employed here is preferably an ether such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether (particularly tetrahydrofuran).

The present reaction is preferably carried out under an inert gas streamsuch as nitrogen, helium or argon.

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is preferably from −78° C. to roomtemperature.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc., but it is preferably from 10minutes to 5 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by pouring the reaction mixture into an aqueous ammoniumchloride solution, extracting the mixture with a solvent immiscible withwater, for example, benzene, ether or ethyl acetate, and evaporating thesolvent from the extract. The thus obtained desired compound can befurther purified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography.

(Reaction B-1c)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting materialto-some extent, and may be an aliphatic hydrocarbon such as hexane,cyclohexane, heptane, ligroin or petroleum ether; an aromatichydrocarbon such as benzene, toluene or xylene; an ether such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; an ester such as methyl acetate orethyl acetate; or an alcohol such as methanol, ethanol, propanol,isopropanol, butanol or isobutanol, and is preferably an ester(particularly ethyl acetate) or an alcohol (particularly methanol).

The catalytic reduction catalyst to be employed here is not particularlylimited so long as it is used for usual catalytic reduction reactions,and may be palladium black, palladium-carbon, palladium hydroxide,palladium hydroxide-carbon, Raney nickel, rhodium-aluminum oxide,palladium-barium sulfate, platinum oxide or platinum black, and ispreferably palladium-carbon.

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −10° C. to 100° C., preferablyfrom 0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 10 minutes to 48 hours,preferably from 30 minutes to 24 hours.

After the reaction, the desired compound is collected from the reactionmixture according to conventional methods. For example, after completionof the reaction, the desired compound is obtained by removing thecatalyst by filtration and evaporating the filtrate. The thus obtaineddesired compound can be further purified, if necessary, by conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Step B-2)

This step is to prepare the compound (I) by carrying out, if necessary,a deprotection reaction of the protecting group, an N-alkylationreaction of the amine, and a carbamoylation reaction of the hydroxylgroup of the compound (V) obtained in Step B-1.

The present step is carried out similarly to Step A-2.

(Process C)

(Step C-1)

This step is to prepare the compound (VII) by reducing the carbonylgroup of the compound (VI) obtained by Process F or Process G describedlater (Reaction C-1a), further halogenating the obtained hydroxyl group(Reaction C-1b) and thereafter aminating it (Reaction C-1c).

(Reaction C-1a)

The reducing agent to be employed here is preferably a hydride compoundsuch as lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride, more preferably sodium borohydride.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an ether such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane; or an alcohol such asmethanol or ethanol, and is preferably an ether (particularlytetrahydrofuran) or an alcohol (particularly methanol).

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −78° C. to 100° C.,preferably from −78° C. to room temperature.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 10 minutesto 24 hours, preferably from one to 10 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by appropriatelyneutralizing the reaction mixture, or, in the case where insolublesexist, removing them by filtration, adding an organic solvent immisciblewith water such as ethyl acetate, washing with water, separating theorganic layer containing the desired compound, drying with anhydrousmagnesium sulfate, and evaporating the solvent. The thus obtaineddesired compound can be further purified, if necessary, by conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Reaction C-1b)

The phosphine to be employed here may be a tri-C₁-C₆ alkylphosphine suchas trimethylphosphine, triethylphosphine, tripropylphosphine,tributylphosphine, tripentylphosphine or trihexylphosphine; a tri-C₆-C₁₀arylphosphine such as triphenylphosphine, triindenylphosphine ortrinaphthylphosphine; or a tri-C₆-C₁₀ arylphosphine which may have aC₁-C₄ alkyl substituent, such as tolyldiphenylphosphine,tritolylphosphine, trimesitylphosphine, tributylphenylphosphine ortri-6-ethyl-2-naphthylphosphine, and is preferably a tri-C₁-C₆alkylphosphine (particularly trimethylphosphine, triethylphosphine,tripropylphosphine or tributylphosphine) or a tri-C₆-C₁₀ arylphosphine(particularly triphenylphosphine, triindenylphosphine ortrinaphthylphosphine), more preferably a tri-C₆-C₁₀ arylphosphine(particularly triphenylphosphine).

The halogenating agent to be employed is a carbon tetrahalide such ascarbon tetrabromide.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,heptane, ligroin or petroleum ether; an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile; anamide such as formamide, dimethylformamide dimethylacetamide,hexamethylphosphoramide (HMPA) or hexamethylphosphorus triamide (HMPT);or a sulfoxide such as dimethyl sulfoxide or sulfolane, and ispreferably a halogenated hydrocarbon.

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −10° C. to 100° C., preferablyfrom 0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 5 minutes to-10 hours,preferably from 10 minutes to 3 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by appropriatelyneutralizing the reaction mixture, and, in the case where insolublesexist, removing them by filtration, adding an organic solvent immisciblewith water such as ethyl acetate, washing with water, separating theorganic layer containing the desired compound, drying with anhydrousmagnesium sulfate or the like and evaporating the solvent. The thusobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography.

(Reaction C-1c)

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,heptane, ligroin or petroleum ether; an aromatic hydrocarbon such asbenzene, toluene or xylene; an ether such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycoldimethyl ether; an alcohol such as methanol or ethanol; a nitrile suchas acetonitrile; an amide such as formamide, dimethylformamide,dimethylacetamide, hexamethylphosphoramide (HMPA) orhexamethylphosphorus triamide (HMPT); or a sulfoxide such as dimethylsulfoxide or sulfolane, and is preferably an alcohol.

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from 0° C. to 150° C., preferably from0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 5 minutes to 24 hours,preferably from one hour to 24 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by adding water to thereaction mixture, adding a solvent immiscible with water (for example,benzene, ether, ethyl acetate, etc.) to extract the desired compound,washing the extracted organic layer with water, drying with anhydrousmagnesium sulfate or the like and evaporating the solvent. The thusobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography.

(Step C-2)

This step is to prepare the compound (I) by carrying out, if necessary,a deprotection reaction of the protecting group, an N-alkylationreaction of the amine, and a carbamoylation reaction of the hydroxylgroup of the compound (VII) obtained in Step C-1.

The present-step is carried out similarly to Step A-2.

The compound (II) used in the above Process A and Process B can beobtained by the following Process D, Process E, Process H, Process I orProcess J, and the compound (VI) used in Process C can be obtained bythe following Process F or Process G.

In the above schemes, R⁵, R^(2a), R^(3a), R^(b), A, Arom^(a), E^(c), Land X² have the same meanings as defined above, Alk represents a C₁-C₆alkyl group, Hal represents a halogen atom, L^(a) indicates the above Lor a protected hydroxyl group, n represents an integer of from 0 to 4, mrepresents an integer of from 1 to 6 and p represents an integer of from1 to 3.

The protecting group for the hydroxyl group in L^(a) is not particularlylimited so long as it can stably protect the hydroxyl group during thereaction, and specifically means a protecting group which is cleavableby a chemical method such as hydrogenolysis, hydrolysis, electrolysisand photolysis, and may include the above “aliphatic acyl group”; theabove “aromatic acyl group”; the above “tetrahydropyranyl ortetrahydrothiopyranyl group”; the above “silyl group” the above“alkoxymethyl group”; the above “substituted ethyl group”; the above“aralkyl group”; the above “alkoxycarbonyl group”; the above“alkenyloxycarbonyl group”; and the above “aralkyloxycarbonyl group”.

In the following, Process D to Process J are described in detail.

(Process D)

(Step D-1)

This step is to prepare the compound (X) by reacting the compound (VIII)which is publicly known or easily obtainable from publicly knowncompounds, the compound (IX) and malonic acid.

The present step is accomplished by reacting the compounds according tothe method described in Helv. Chim. Acta, 68, 403 (1985).

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,cyclohexane, heptane, ligroin or petroleum ether; an aromatichydrocarbon such as benzene, toluene or xylene; a halogenatedhydrocarbon such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, chlorobenzene or dichlorobenzene; an ether such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether; an ester such asmethyl acetate or ethyl acetate; or an alcohol such as methanol,ethanol, propanol, isopropanol, butanol or isobutanol, and is preferablyan alcohol (particularly ethanol or propanol).

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from 0° C. to 150° C., preferably from50° C. to 100° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 30 minutes to 24 hours,preferably from one hour to 12 hours.

After the reaction, the desired compound is collected from the reactionmixture according to conventional-methods. For example, after completionof the reaction, the desired compound is obtained by collecting byfiltration. The desired compound of the present step can be used for thesubsequent step without purification.

In the desired compound of the present reaction, if necessary, aprotecting group can be introduced onto the hydroxyl group and the aminogroup according to known methods (for example, the methods described in“Protective Groups in Organic Synthesis” (written by Theodora W. Geene,Peter G. M. Wuts, 1999 published by A Wiley-Interscience Publication)).The reaction for introducing the protecting group may be carried out inan arbitrary step other than the present step, and a person skilled inthe art, when introducing the protecting group, can easily select anappropriate step depending on the desired compound.

Namely, in the case where a protecting group is introduced onto thehydroxyl group, for example, the step is carried out as follows.

The compound employed for protecting the hydroxyl group may be anaralkyl halide compound such as benzyl chloride, benzyl bromide,4-nitrobenzyl bromide or 4-methoxybenzyl bromide; an alkoxy-, alkylthio-or aralkyloxy-substituted alkyl halide compound such as methoxymethylchloride, methylthiomethyl chloride, ethoxyethyl chloride orbenzyloxymethyl chloride; an unsaturated ether such as methylvinyl etheror ethylvinyl ether; or a silyl compound such as hexamethyldisilazane,trimethylsilyl chloride, tri-n-propylsilyl chloride,t-butyldimethylsilyl chloride or diphenyl-t-butylsilyl chloride, as thepreferred compounds.

The reagent employed here may be an organic base such as triethylamine,pyridine, 4-N,N-dimethylaminopyridine, imidazole or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); or an inorganic base such assodium hydroxide, potassium hydroxide or potassium carbonate. In thecase where an unsaturated ether is used, the reaction is carried out inthe presence of a small amount of an acid, for example, a mineral acidsuch as hydrochloric acid or hydrobromic acid, or an organic acid suchas picric acid, trifluoroacetic acid, benzenesulfonic acid,4-toluenesulfonic acid or camphorsulfonic acid in the presence orabsence of an inert solvent. The solvent to be employed here is notparticularly limited so long as it does not inhibit the reaction anddissolves the starting material to some extent, and may be an ether suchas ether, tetrahydrofuran or dioxane; an amide such as formamide,dimethylformamide or dimethylacetamide; a halogenated hydrocarbon suchas dichloromethane, chloroform or carbon tetrachloride; or an aromatichydrocarbon such as benzene, toluene or xylene, and is preferably anamide (particularly dimethylformamide) or a halogenated hydrocarbon. Thereaction can also be carried out by using an excess amount of vinylether compound to act also as the solvent in the absence of an inertsolvent.

The reaction temperature varies depending on the-solvent, startingmaterial, reagent, reaction temperature, etc., but it is usually from 0°C. to 50° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc. but it is usually from 30 minutes to3 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by appropriatelyneutralizing the reaction mixture, and, in the case where insolublesexist, removing them by filtration, adding an organic solvent immisciblewith water such as ethyl acetate, washing with water, separating theorganic layer containing the desired compound, drying with anhydrousmagnesium sulfate or the like and evaporating the solvent. The thusobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography.

In the case where a protecting group is introduced onto the amino group,the step is, for example, carried out as follows.

The introduction of the protecting group is accomplished by <Method 1>in which the compound is reacted with from 1 to 4 equivalents(preferably from 2 to 3 equivalents) of a compound of formula: P¹-LG ora compound of formula: P¹-O-P¹ (in the case where P¹ is an acyl group)in the presence or absence of a base (preferably in the absence ofa-base) in an inert solvent; or <Method 2> in which the compound isreacted with a compound of formula: P¹—OH (in the case where P¹ is anacyl group) in the presence of a condensing agent and in the presence orabsence of a catalytic amount of base (preferably in the presence ofboth) in an inert solvent; or <Method 3> in which the compound isreacted with a compound of formula: P¹—OH (in the case where P¹ is anacyl group) in the presence of a halogenated phosphoric acid dialkylester (preferably diethyl chlorophosphate) and a base in an inertsolvent.

In the above, the leaving group LG may be a group similar to thosedescribed above.

The compound of formula: P¹-LG used in the above <Method 1> may bet-butoxycarbonyl chloride, t-butoxycarbonyl bromide,2-trimethylsilylethoxycarbonyl chloride, 2-trimethylsilylethoxycarbonylbromide, p-methoxybenzyloxycarbonyl chloride, p-methoxybenzyloxycarbonylbromide, allyloxycarbonyl chloride or allyloxycarbonyl bromide, and ispreferably t-butoxycarbonyl chloride.

The compound of formula: P¹—O—P¹ used in <Method 1> may be di-t-butyldicarbonate, 2-trimethylsilylethoxycarboxylic anhydride,p-methoxybenzyloxycarboxylic acid or allyloxycarboxylic anhydride, andis preferably di-t-butyl dicarbonate.

The solvent employed in <Method 1> is not particularly limited so longas it does not inhibit the reaction and dissolves the starting materialto some extent, and may be an aliphatic hydrocarbon such as hexane orheptane; an aromatic hydrocarbon such as benzene, toluene or xylene; ahalogenated hydrocarbon such as dichloromethane, chloroform, carbontetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; anester such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; or an amide such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone orhexamethylphosphoric triamide, and is preferably an ether (particularlydiethyl ether or tetrahydrofuran) or a halogenated hydrocarbon(particularly dichloromethane).

The base employed in <Method 1> may be an organic amine such asN-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine,dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine,picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(tert-butyl)-4-methylpyridine, imidazole, quinoline,N,N-dimethylaniline or N,N-diethylaniline, and is preferablytriethylamine or 4-(N,N-dimethylamino)pyridine.

A catalytic amount of 4-(N,N-dimethylamino)pyridine or4-pyrrolidinopyridine can be also used in combination with other bases,and a quaternary ammonium salt such as benzyltriethylammonium chlorideor tetrabutylammonium chloride or a crown ether such asdibenzo-18-crown-6 can be also added in order to effectively carry outthe reaction.

The reaction temperature in <Method 1> is usually from −20° C. to 100°C., preferably from −10° C. to 50° C.

The reaction time in <Method 1> mainly varies depending on the reactiontemperature, starting compound, base used and kind of solvent used, butit is usually from 10 minutes to one day, preferably from 30 minutes to12 hours.

The compound of formula: P¹—OH employed in the above <Method 2> and<Method 3> may be t-butoxycarboxylic acid,2-trimethylsilylethoxycarboxylic acid, p-methoxybenzyloxycarboxylic acidor allyloxycarboxylic acid, and is preferably pivalic acid.

The solvent employed in the above <Method 2> is not particularly limitedso long as it does not inhibit the reaction and dissolves the startingmaterial to some extent, and may be an aliphatic hydrocarbon such ashexane or heptane; an aromatic hydrocarbon such as benzene, toluene orxylene; a halogenated hydrocarbon such as dichloromethane, chloroform,carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene;an ester such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; or an amide such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone orhexamethylphosphoric triamide, and is preferably a halogenatedhydrocarbon (dichloromethane or carbon tetrachloride) or an ether(particularly diethyl ether, tetrahydrofuran or dioxane).

The condensing agent employed in <Method 2> may bedicyclohexylcarbodiimide, carbonyldimidazole or1-methyl-2-chloro-pyridinium iodide-triethylamine, and f is preferablydicyclohexylcarbodiimide.

The base employed in <Method 2> can be one which is similar to the baseemployed in the above <Method 1>, preferably triethylamine or4-(N,N-dimethylamino)pyridine.

The reaction temperature in <Method 2> is usually from −20° C. to 80°C., preferably from 0° C. to 30° C.

The reaction time in <Method 2> varies depending mainly on the reactiontemperature, starting compound, reaction reagent and kind of solventused, but it is usually from 10 minutes to 3 days, preferably from 30minutes to one day.

The solvent employed in the above <Method 3> is not particularly limitedso long as it does not inhibit the reaction and dissolves the startingmaterial to some extent, and may be an aliphatic hydrocarbon such ashexane or heptane; an aromatic hydrocarbon such as benzene, toluene orxylene; a halogenated hydrocarbon such as dichloromethane, chloroform,carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene;an ester such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; or an amide such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone orhexamethylphosphoric triamide, and is preferably an ether (diethyl etheror tetrahydrofuran) or an amide (N,N-dimethylformamide orN,N-dimethylacetamide).

The base employed in <Method 3> can be, for example, one which issimilar to the base employed in the above <Method 1>, preferablytriethylamine or 4-(N,N-dimethylamino)pyridine.

The reaction temperature in <Method 3> is from 0° C. to the refluxtemperature of the solvent used, preferably from 20° C. to 50° C.

The reaction time in <Method 3> varies depending mainly on the reactiontemperature, starting compound, reaction reagent and kind of solventused, but it is usually from 10 minutes to 3 days, preferably from 30minutes to one day.

After the reaction, the desired compound obtained by the above method iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by evaporating the solvent or by pouring water onto the residueafter the solvent is evaporated, adding a solvent immiscible with water(for example, benzene, ether, ethyl acetate, etc.) to extract thedesired compound, washing the extracted organic layer with water,followed by drying with anhydrous magnesium sulfate or the like andevaporating the solvent. The thus obtained desired compound can befurther purified, if necessary, according to conventional methods, forexample, recrystallization, reprecipitation or chromatography.

(Step D-2)

This step is to prepare the compound (XI) by esterifying the carboxylgroup of the compound (X) obtained in Step D-1.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be water; an aliphatic hydrocarbon such as hexane,heptane, ligroin or petroleum ether; an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ester such as ethyl formate, ethylacetate, propyl acetate, butyl acetate or diethyl carbonate; an ethersuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether; a nitro compoundsuch as nitroethane or nitrobenzene; a nitrile such as acetonitrile orisobutyronitrile; an amide such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; or a sulfoxide suchas dimethyl sulfoxide or sulfolane. In the present reaction, anesterifying agent such as ethanol can be used as the solvent.

The esterifying reagent to be employed here may be a combination of analcohol such as methanol or ethanol and an inorganic acid such assulfuric acid; an alkylated inorganic acid such as dimethylsulfuricacid; or an alkyldiazo compound such as diazomethane.

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from 0° C. to 150° C., preferably from20° C. to 100° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 30 minutes to 24 hours,preferably from one hour to 12 hours.

After the reaction, the desired compound is collected from the reactionmixture according to conventional methods. For example, after completionof the reaction, the desired compound is obtained by collecting throughfiltration. Or, for example, after completion of the reaction, thedesired compound is obtained by adding water to the reaction solution,adding a solvent immiscible with water (for example, benzene, ether,ethyl acetate, etc.) to extract the desired compound, washing theextracted organic layer with water, drying with anhydrous magnesiumsulfate or the like and evaporating the solvent. The thus obtaineddesired compound can be further purified, if necessary, by conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Step D-3)

This step is to prepare the compound (II) by reducing the ester of thecompound (XI) obtained in Step D-2.

The reducing agent to be employed here is preferably a hydride compoundsuch as lithium aluminum hydride, sodium borohydride, lithiumborohydride or diisobutyl aluminum hydride, more preferably lithiumaluminum hydride.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an ether such as diethyl ether, tetrahydrofuran,dioxane or dimethoxyethane, and is preferably an ether (particularlytetrahydrofuran).

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −78° C. to 100° C.;preferably from −78° C. to room temperature.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 10 minutesto 24 hours, preferably from one hour to 10 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by appropriatelyneutralizing the reaction mixture and, in the case where insolublesexist, removing them by filtration, adding an organic solvent immisciblewith water such ethyl acetate, washing with water, separating theorganic layer containing the desired compound, drying with anhydrousmagnesium sulfate or the like and evaporating the solvent. The thusobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography.

In the case where A of the desired compound is a group other than amethylene group, after the hydroxyl group moiety is further substitutedfor a cyano group (Reaction D-3a) and converted into a formyl group byreduction (Reaction D-3b), it is further reduced to a hydroxyl group(Reaction D-3c). Thereby, it can be converted into an ethylene group inwhich the number of carbons is increased by one, and the desiredcompound (II) can be prepared by repeating this step a plurality oftimes.

Further, in the case where the desired compound is cyclized, the desiredcompound (II) can be prepared by carrying out a cyclization reaction(D-3d).

(Reaction D-3a)

The present reaction is accomplished by (α) reacting an alkyl orarylsulfonyl halide (preferably methanesulfonyl chloride) with thehydroxyl group of the compound and (β) reacting the product with analkyl metal cyanide (preferably sodium cyanide or potassium cyanide).

(α) Reaction of Hydroxyl Group with a Sulfonyl Halide

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an aromatic hydrocarbon such asbenzene; a halogenated hydrocarbon such as dichloromethane orchloroform; or an ether such as diethyl ether, tetrahydrofuran, dioxaneor dimethoxyethane, and is preferably an ether (particularlytetrahydrofuran).

The base to be employed here may be an organic base such astriethylamine, diisopropylamine, isopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline or N,N-diethylaniline, and is preferablytriethylamine.

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −20 to 50° C.,preferably from 0 to 25° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 5 minutes to10 hours, preferably from 10 minutes to 3 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by adding water to the reaction solution, adding a solventimmiscible with water (for example, benzene, ether, ethyl acetate, etc.)to extract the desired compound, washing the extracted organic layerwith water, drying with anhydrous magnesium sulfate or the like andevaporating the solvent. The thus obtained desired compound can befurther purified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography. The desiredcompound of the present step can be used for the subsequent step withoutpurification.

(β) Reaction with Cyanide

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an ether such as tetrahydrofuran, dioxane ordimethoxyethane; a nitrile such as acetonitrile or isobutyronitrile; anamide such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; or a sulfoxide such as dimethyl sulfoxideor sulfolane, and is preferably an amide (particularlydimethylformamide).

In the present reaction, crown ether compound can be added. The crownether compound employed here may be 12-crown-4, 15-crown-5, 18-crown-6,1-aza-12-crown-4, 1-aza-15-crown-5, 1-aza-18-crown-6, benzo-15-crown-5,4′-nitrobenzo-15-crown-5, benzo-18-crown-6, dibenzo-18-crown-6,dibenzo-24-crown-8, dicyclohexano-18-crown-6 ordicyclohexano-24-crown-8, and is preferably 15-crown-5, 18-crown-6,1-aza-15-crown-5, 1-aza-18-crown-6, benzo-15-crown-5,4′-nitrobenzo-15-crown-5, benzo-18-crown-6, dibenzo-18-crown-6 ordicyclohexano-18-crown-6, more preferably 15-crown-5, 18-crown-6,1-aza-18-crown-6, benzo-18-crown-6, dibenzo-18-crown-6 ordicyclohexano-18-crown-6, particularly preferably 15-crown-5 or18-crown-6.

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from 0 to 180° C., preferablyfrom 0 to 50° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc. but it is usually from 1 to 24hours, preferably from 2 to 12 hours.

After the reaction, the desired compound of the present step iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by adding water to the reaction solution, adding a solventimmiscible with water (for example, benzene, ether, ethyl acetate, etc.)to extract the desired compound, washing the extracted organic layerwith water, drying with anhydrous magnesium sulfate or the like andevaporating the solvent. The thus obtained desired compound can befurther purified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography.

(Reaction D-3b)

The reducing agent employed here is preferably diisobutyl aluminumhydride.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an ether such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane; a halogenated hydrocarbonsuch as dichloromethane, chloroform or dichloroethane; an aromatichydrocarbon such as benzene, toluene or xylene; or an aliphatichydrocarbon such as pentane or hexane, and is more preferably ahalogenated hydrocarbon such as dichloromethane.

The present step is preferably carried out under an inert gas streamsuch as nitrogen, helium or argon.

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −78° C. to 50° C.,preferably from −20° C. to room temperature.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 10 minutesto 24 hours, preferably from one to 5 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by appropriatelyneutralizing the reaction mixture and, in the case where insolublesexist, removing them by filtration, adding a solvent immiscible withwater such as ethyl acetate, washing with water, separating the organiclayer containing the desired compound, drying with anhydrous magnesiumsulfate or the like and evaporating the solvent. The thus obtaineddesired compound can be further purified, if necessary, by conventionalmethods, for example, recrystallization, reprecipitation orchromatography. The desired compound of the present step can be used forthe subsequent step without purification.

(Reaction D-3c)

The reducing agent to be employed here is preferably a hydride compoundsuch as lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride, more preferably sodium borohydride.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an ether such as diethyl ether,tetrahydrofuran, dioxane or dimethoxyethane; or an alcohol such asmethanol or ethanol, and is preferably an ether (particularlytetrahydrofuran) or an alcohol (particularly methanol).

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from −78° C. to 100° C.,preferably from −78° C. to room temperature.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 10 minutesto 24 hours, preferably from one to 10 hours.

After completion of the reaction, the desired compound of the presentreaction is collected from the reaction mixture according toconventional methods. For example, the desired compound is obtained byappropriately neutralizing the reaction mixture and, in the case whereinsolubles exist, removing them by filtration, adding an organic solventimmiscible with water such as ethyl acetate, washing with water,separating the organic layer containing the desired compound, dryingwith anhydrous magnesium sulfate or the like and evaporating thesolvent. The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation or chromatography.

A leaving group can be introduced, if necessary, to the desired compoundof the present reaction by known methods.

Namely, in the case where the leaving group is a halogen atom, thedesired compound can be obtained according to the process of (ReactionC-1b), and in the case where the leaving group is a sulfonyloxy group,the desired compound can be obtained according to the method of(Reaction D-3a) (α).

(Reaction D-3d)

This reaction is carried out similarly to (Reaction A-2d).

The present reaction may be carried out at any stage of the reductionreaction of the ester or (Reaction D-3a) to (Reaction D-3c), dependingon the desired compound.

(Process E)

(Step E-1)

This step is to prepare the compound (XII) by enolating an acetatederivative with a base, followed by reacting with the compound (VIII),which is publicly known or easily obtainable from known compounds.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,cyclohexane, heptane, ligroin or petroleum ether; an aromatichydrocarbon such as benzene, toluene or xylene; an ether such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; an amide such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide orN-methyl-2-pyrrolidinone; or a sulfoxide such as dimethyl sulfoxide orsulfolane, and is preferably an alcohol (particularly methanol orethanol).

The base may be an alkali metal hydroxide such as lithium hydroxide,sodium hydroxide or potassium hydroxide; an alkali metal hydride such aslithium hydride, sodium hydride or potassium hydride; an alkyl lithiumsuch as methyl lithium, ethyl lithium or butyl lithium; or a lithiumalkylamide such as lithium diisopropylamide, lithium dicyclohexylamideor lithium bis(trimethylsilyl)amide, and is preferably an alkali metalhydroxide (particularly potassium hydroxide).

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −100° C. to 50° C., preferablyfrom 0° C. to room temperature.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 5 minutes to 24 hours,preferably from one hour to 12 hours.

After the reaction, the desired compound is collected from the reactionmixture according to conventional methods. For example, after completionof the reaction, the desired compound is obtained by adding water to thereaction solution, adding a solvent immiscible with water (for example,benzene, ether, ethyl acetate, etc.) to extract the desired compound,washing the extracted organic layer with water, drying with anhydrousmagnesium sulfate or the like and evaporating the solvent. The thusobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography. A plurality of compounds can sometimes be obtained inthe present step but it can be easily judged by a person skilled in theart which compound is the desired compound by using the usual means (forexample, measurement of a coupling constant in NMR spectrum, etc.) andthe desired compound can be obtained.

(E-2)

The present step is to prepare the compound (XI) by carrying out aMichael addition using a metal amide on the compound (XII).

The present step can be accomplished by the addition reaction of themetal amide derived from benzylphenylethylamine described inTetrahedron; Asymmetry, 2, 183 (1991).

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic hydrocarbon such as hexane,cyclohexane, heptane, ligroin or petroleum ether; an aromatichydrocarbon such as benzene, toluene or xylene; an ether such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; or an amide such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,N-methylpyrrolidinone or hexamethylphosphoric triamide, and ispreferably an ether (particularly tetrahydrofuran).

The reaction is carried out in the presence of a base. The base to beemployed here may be an alkyl lithium such as methyl lithium or butyllithium; an alkali metal disilazide such as lithiumhexamethyldisilazide, sodium hexamethyldisilazide or potassiumhexamethyldisilazide; or a lithium amide such as lithiumdiisopropylamide or lithium dicyclohexylamide, and is preferably analkyl lithium (particularly butyl lithium).

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −78° C. to 40° C., preferably from−78° C. to 0° C.

The reaction time varies depending on the starting compound, reagent,and reaction temperature, but it is usually from 10 minutes to 24 hours,preferably from 10 minutes to 4 hours.

After the reaction, the desired compound is collected from the reactionmixture according to conventional methods. For example, after completionof the reaction, the desired compound is obtained by removing thecatalyst by filtration and evaporating the filtrate. The thus obtaineddesired compound can be further purified, if necessary, by conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Step E-3)

This step is to prepare the compound (II) by reducing the ester of thecompound (XI) obtained in Step E-2.

The present step is carried out similarly to Step D-3

(Process F)

(Step F-1)

This step is to prepare the compound (XIV) by enolating the compound(XII), which is publicly known or easily obtainable from publicly knowncompounds, with a base, followed by reacting with an aldehyde.

The present reaction is carried out similarly to Step E-1.

(Step F-2)

This step is to prepare the compound (VI) by reducing the compound (XIV)obtained in Step F-1.

The present step is carried out similarly to (Reaction B-1c).

(Process G)

(Step G-1)

This step is to prepare the compound (XIV) by reacting the compound(XV), which is publicly known or easily obtainable from publicly knowncompounds, with a compound of the formula: R³-E^(c)-H (wherein R³ andE^(c) have the same meanings as defined above) in the presence of abase.

The present step is carried out similarly to Step A-1.

(Step G-2)

This step is a step in which the ester of the compound (XVI) obtained inG-1 is hydrolized (Reaction G-2a) and is then amidated (Reaction G-2b).

(Reaction G-2a)

The base may preferably be an alkali metal carbonate such as sodiumcarbonate or potassium carbonate; an alkali metal hydroxide such assodium hydroxide or potassium hydroxide; or a concentratedammonia-methanol solution.

The solvent to be employed here may preferably be water; or a mixture ofan organic solvent such as an alcohol, e.g., methanol, ethanol orn-propanol, or an ether, e.g., tetrahydrofuran or dioxane, and water.

The reaction temperature and the reaction time vary depending on thestarting material, solvent and reagent used, but the reaction is usuallycarried out at from 0° C. to 150° C. for from one to 10 hours in orderto inhibit side reactions.

After the reaction, the desired compound is collected from the reactionmixture according to conventional methods. For example, after completionof the reaction, the desired compound is obtained by evaporating thefiltrate. The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation or chromatography.

(Reaction G-2b)

The reaction is carried out according to conventional methods in peptidesynthesis, for example, by an activated ester method, a mixed acidanhydride method, or a condensation method.

-   1) The activated ester method is carried out by reacting the    compound with an active esterifying agent in an inert solvent to    prepare an active ester and reacting it with    N,O-dimethylhydroxylamine in an inert solvent.

The active esterifying agent employed here may be an N-hydroxy compoundsuch as N-hydroxysuccinimide, 1-hydroxybenzotriazole orN-hydroxy-5-norbornene-2,3-dicarboximide; or a disulfide compound suchas dipyridyl disulfide. Furthermore, the active esterification reactionis preferably carried out in the presence of a condensing agent such asdicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.

The solvent to be employed in both reactions is not particularly limitedso long as it does not inhibit the reaction and dissolves the startingmaterial to some extent, and may be a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; a nitrile such as acetonitrile orisobutyronitrile; or an amide such as formamide, dimethylformamide,dimethylacetamide, hexamethylphosphoramide (HMPA) orhexamethylphosphorus triamide (HMPT), and is preferably an ether(particularly. tetrahydrofuran), a nitrile (particularly acetonitrile)or an amide (particularly dimethylformamide).

The reaction temperature varies depending on the starting compound,reagent, etc., but it is usually from −20° C. to 100° C. for the activeesterification reaction, preferably from 0° C. to 50° C. For thereaction with the active ester compound, it is from −20° C. to 100° C.,preferably from 0° C. to 50° C.

The reaction time varies depending on the starting compound, reagent andreaction temperature, but it is usually from 30 minutes to 24 hours inboth reactions, preferably from 1 to 12 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by evaporating the solvent, or pouring water onto the residuefrom which the solvent has been evaporated, adding a solvent immisciblewith water (for example, benzene, ether, ethyl acetate, etc.) to extractthe desired compound, washing the extracted organic layer with water,drying with anhydrous magnesium sulfate or the like and evaporating thesolvent. The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation or chromatography.

-   2) Next, the mixed acid anhydride method is carried out by reacting    the compound with a mixed acid anhydride forming agent in the    presence or absence of a base (preferably in the presence of a base)    in an inert solvent to prepare a mixed acid anhydride, and reacting    the mixed acid anhydride with N,O-dimethylhydroxylamine in an inert    solvent.

The mixed acid anhydride forming agent employed here may be an oxalylhalide such as oxalyl chloride; a chloroformic acid C1-C5 ester such asethyl chloroformate or isobutyl chloroformate; a C1-C5 alkanoyl halidesuch as pivaloyl chloride; or a C1-C4 alkyl or di-C6-C14arylcyanophosphoric acid such as diethylcyanophosphoric acid ordiphenylcyanophosphoric acid, and is preferably an oxalyl halide(particularly oxalyl chloride).

The reaction is carried out in the presence or absence of a base, but itis preferably carried out in the presence of a base. The base employedhere may be an alkali metal carbonate such as sodium carbonate,potassium carbonate or lithium carbonate; or an organic amine such astriethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline,N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane (DABCO), or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferably an organicamine (particularly triethylamine).

The reaction to prepare the mixed acid anhydride is preferably carriedout in the presence of a solvent. The solvent to be employed here is notparticularly limited so long as it dissolves the starting material tosome extent, and may be a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; or an amide such as formamide,dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA), orhexamethylphosphorus triamide (HMPT), and is preferably a halogenatedhydrocarbon (particularly dichloromethane).

The reaction temperature for the reaction to prepare the mixed acidanhydride varies depending on the starting compound, reagent, etc., butit is usually from −50° C. to 100° C., preferably from −10° C. to 50 °C.

The reaction time for the reaction to prepare the mixed acid anhydridevaries depending on the starting compound, reagent and reactiontemperature, but it is usually from 5 minutes to 20 hours, preferablyfrom 10 minutes to 10 hours.

Next, the solvent to be employed for the reaction of the mixed acidanhydride and N,O-dimethylhydroxylamine is not particularly limited solong as it does not inhibit the reaction and dissolves the startingmaterial to some extent, and may be an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; or an amide such as formamide,dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPA) orhexamethylphosphorus triamide (HMPT), and is preferably an amide(particularly dimethylformamide).

The reaction temperature for the reaction with the mixed acid anhydridevaries depending on the starting compound, reagent, etc., but it isusually from −30° C. to 100° C., preferably from 0° C. to 80° C.

The reaction time for the reaction with the mixed acid anhydride variesdepending on the starting compound, reagent and reaction temperature,but it is usually from 5 minutes to 24 hours, preferably from 10 minutesto 12 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by evaporating the solvent, or pouring water onto the residuefrom which the solvent has been evaporated, adding a solvent immisciblewith water (for example, benzene, ether, ethyl acetate, etc.) to extractthe desired compound, washing the extracted organic layer with water,drying with anhydrous magnesium sulfate or the like and evaporating thesolvent. The thus obtained desired compound can be further purified, ifnecessary, by conventional methods, for example, recrystallization,reprecipitation or chromatography.

-   3) Next, the condensation method is carried out by reacting the    compound with N,O-dimethylhydroxylamine in an inert solvent using a    condensing agent and a base.

The condensing agent employed here may be an azodicarboxylic aciddi-lower alkyl ester-triphenylphosphine such as diethylazodicarboxylate-triphenylphosphine; an N,N′-dicycloalkylcarbodiimidesuch as N,N′-dicyclohexylcarbodiimide (DCC); a 2-halo-1-lower alkylpyridinium halide such as 2-chloro-1-methyl pyridinium iodide; adiarylphosphorylazide such as diphenylphosphorylazide (DPPA); achloroformate such as ethyl chloroformate or isobutyl chloroformate; aphosphoryl chloride such as diethyl phosphoryl chloride; an imidazolederivative such as N,N′-carbodiimidazole (CDI); a carbodiimidederivative such as 1-ethyl-3-(3-diethylaminopropyl)carbodiimidehydrochloride (EDAPC); or a sulfonyl chloride derivative such as2,4,6-triisopropylbenzenesulfonyl chloride, and is preferably DDC, CDI,2-chloro-1-methyl pyridinium iodide, isobutyl chloroformate ordiethylphosphoryl chloride.

The base employed here may be an organic base such as triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, 4-pyrrolidinopyridine,N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO),or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferablytriethylamine, diisopropylethylamine, pyridine or 4-pyrrolidinopyridine.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may preferably be an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such asdichloromethane, chloroform or dichloroethane; an ester such as ethylacetate or propyl acetate; an ether such as diethyl ether,tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether; a ketone such as acetone or methyl ethyl ketone; a nitro compoundsuch as nitromethane; a nitrile such as acetonitrile orisobutyronitrile; or an amide such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide, and is morepreferably a nitrile (particularly acetonitrile), an aromatichydrocarbon (particularly benzene), a halogenated hydrocarbon(particularly dichloromethane), or an ether (particularlytetrahydrofuran).

The reaction temperature varies depending on the solvent, startingmaterial, reagent, etc., but it is usually from 0° C. to 150° C.,preferably from 25° C. to 120° C.

The reaction time varies depending on the solvent, starting material,reagent, reaction temperature, etc., but it is usually from 10 minutesto 48 hours, preferably from one to 24 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by adding an organicsolvent immiscible with water such as ethyl acetate to the reactionmixture, washing with water, separating the organic layer containing thedesired compound, drying with anhydrous magnesium sulfate or the likeand evaporating the solvent. The thus obtained desired compound can befurther purified, if necessary, according to conventional methods, forexample, recrystallization, reprecipitation or chromatography.

(Step G-3)

This step is to prepare the compound (VI) by reacting the carbanionobtained by treatment of the compound (XVIII) with a base, with thecompound (XVII) obtained in Step G-2.

When the compound (XVIII) is treated with a base, the base employed maybe an alkyl lithium such as methyl lithium, butyl lithium, s-butyllithium or t-butyl lithium, and is preferably butyl lithium, s-butyllithium or t-butyl lithium, more preferably butyl lithium.

The solvent to be employed here is not particularly limited so long asit does not inhibit the reaction and dissolves the starting material tosome extent, and may be an aliphatic or alicyclic hydrocarbon such ashexane or cyclohexane; an aromatic hydrocarbon such as benzene; tolueneor xylene; or an ether such as diethyl ether, tetrahydrofuran ordioxane, and is preferably an aromatic hydrocarbon or an ether, morepreferably an ether (particularly tetrahydrofuran).

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from −78° C. to 0° C.,preferably from −78° C. to −20° C.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc. but it is usually from 10 minutes to24 hours, preferably from 10 minutes to 6 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by pouring the reaction mixture into an aqueous solution suchas a cooled saturated aqueous ammonium chloride solution, adding asolvent immiscible with water (for example, benzene, ether, ethylacetate, etc.) to extract the desired compound, washing the extractedorganic layer with water, drying with anhydrous magnesium sulfate or thelike and evaporating the solvent. The thus obtained desired compound canbe further purified, if necessary, by conventional methods, for example,recrystallization, reprecipitation or chromatography.

(Process H)

(Step H-1)

This step is one in which after an aldol condensation reaction iscarried out on the compound (VIII), which is publicly known or easilyobtainable from publicly known compounds (Reaction H-1a), the ester isreduced (Reaction H-1b) and the produced primary alcohol is protected,if necessary (Reaction H-1c).

(Reaction H-1a)

The present reaction is carried out by firstly treating the reagent witha base to prepare an organic anionic reagent and adding the compound(VIII) thereto.

The solvent to be employed here may be an aliphatic hydrocarbon such ashexane, heptane, ligroin or petroleum ether; an aromatic hydrocarbonsuch as benzene, toluene or xylene; a halogenated hydrocarbon such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; or an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, and is preferably an ether(particularly tetrahydrofuran).

The reagent employed in the present reaction is not particularly limitedso long as it can be used for aldol condensations, but it is preferablyethyl acetate.

The base employed here may be an alkali metal hydride such as lithiumhydride, sodium hydride or potassium hydride; an alkali metal hydroxidesuch as sodium hydroxide, potassium hydroxide, barium hydroxide orlithium hydroxide; or an organometal base such as butyl lithium, lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide, and is preferablyan organometal base (particularly lithium bis(trimethylsilyl)amide).

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from −100° C. to 50° C.,preferably from −78° C. to 0° C.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc. but it is usually from 5 minutes to12 hours, preferably from 30 minutes to 10 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by collecting the desiredcompound precipitated in the reaction solution by filtration, orappropriately neutralizing the reaction solution, evaporating thesolvent, pouring water into the reaction solution, adding a solventimmiscible with water (for example, benzene, ether, ethyl acetate, etc.)to carry out an extraction, washing the organic layer containing thedesired compound with water, drying with anhydrous magnesium sulfate orthe like and evaporating the solvent. The thus obtained desired compoundcan be further purified, if necessary, according to conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Reaction H-1b)

This reaction is carried out similarly to the reduction reaction of theester in Step D-3.

(Reaction H-1c)

This reaction is carried out similarly to the protection reaction of thehydroxyl group in Step D-2.

In the present step, the desired R^(b) can be obtained by carrying out asimilar reaction to (α) in (Reaction A-2d), if necessary.

(Step H-2)

This step is to prepare the compound (II) by reacting the compound (IX)with the compound (XIV) obtained in Step H-1 (Reaction H-2a); and thencarrying out similar reactions (Reaction H-2b) to those in (ReactionD-3a) to (Reaction D-3d).

(Reaction H-2a)

This step is accomplished by carrying a reaction similar to <Method 1>of (Reaction A-1a), or carrying out a reaction similar to (β) of <Method1> of (Reaction A-1a), after carrying out a reaction similar to(Reaction C-1b).

(Reaction H-2b)

This reaction is carried out similarly to (Reaction D-3a) to (ReactionD-3d).

(Process I)

(Step I-1)

This step is to prepare the compound (IIa) by carrying out an acylationreaction (Reaction I-1a) on the compound (XV), which is publicly knownor easily obtainable from publicly known compounds, followed by carryingout a Bischler-Napieralski reaction (Reaction I-1b), and by reducing thethus obtained compound (Reaction I-1c).

(Reaction I-1a)

The solvent to be employed here may be an aliphatic hydrocarbon such ashexane, heptane, ligroin or petroleum ether; an aromatic hydrocarbonsuch as benzene, toluene or xylene; a halogenated hydrocarbon such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene; an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy ethane ordiethylene glycol dimethyl ether; an amide such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,N-methylpyrrolidinone or hexamethylphosphoric triamide; or a sulfoxidesuch as dimethyl sulfoxide or sulfolane, and is preferably an amide(particularly dimethylformamide) or a halogenated hydrocarbon(particularly dichloromethane).

The acylating agent employed here is not particularly limited so long asthe produced amide becomes an amide appropriate for theBischler-Napieralski reaction, and is preferably ethylmalonyl chloride.

The base employed here may be an alkali metal carbonate such as sodiumcarbonate, potassium carbonate or lithium carbonate; or an organic basesuch as N-methylmorpholine, triethylamine, tripropylamine,tributylamine, diisopropylethylamine, dicyclohexylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,quinoline, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicylo[2.2.2]octane(DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and is preferablypotassium carbonate or triethylamine.

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from −100° C. to 50° C.,preferably from −78° C. to 0° C.

The reaction time varies depending on the solvent, starting compound,reagent, the reaction temperature, etc., but it is usually from 5minutes to 12 hours, preferably from 30 minutes to 10 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by collecting the desiredcompound precipitated in the reaction solution by filtration, orappropriately neutralizing the reaction solution, evaporating thesolvent, pouring water into the reaction solution, adding a solventimmiscible with water (for example, benzene, ether, ethyl acetate, etc.)to perform an extraction, washing the organic layer containing thedesired compound with water, drying with anhydrous magnesium sulfate orthe like and evaporating the solvent. The thus obtained desired compoundcan be further purified, if necessary, according to conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Reaction I-1b)

This reaction is carried out in phosphorus oxychloride.

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from 25° C. to 120° C.,preferably from 50° C. to 100° C.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc., but it is usually from 5 minutes to48 hours, preferably from one hour to 12 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.

For example the desired compound may be obtained by filtration of thedesired compound precipitated in the reaction solution or by evaporationof the resulting organic layer after appropriately neutralizing thereaction solution, filtering, evaporating the solvent, pouring waterinto the reaction solution, adding a solvent immiscible with water (forexample, benzene, ether, ethyl acetate, etc.) to perform an extraction,washing the organic layer containing the desired compound with water andthen drying with anhydrous magnesium sulfate or the like. The thusobtained desired compound can be further purified, if necessary, byconventional methods, for example, recrystallization, reprecipitation orchromatography.

(Reaction-I-1c)

In this reaction, after a similar reaction to the catalytic reduction in(Reaction A-2a) is carried out, a reaction is carried out similar to(Step D-3).

(Process J)

(Step J-1)

This step is to prepare the compound (IIa) in optically active form byintroducing a chiral auxiliary group to the compound (XVI), which ispublicly known or easily obtainable from publicly known compounds(Reaction J-1a), introducing a side chain thereto (Reaction J-1b), andremoving the chiral auxiliary group (Reaction J-1c).

(Reaction J-1a)

The solvent to be employed here may be an aromatic hydrocarbon such asbenzene, toluene or xylene; or an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, and is preferably an aromatichydrocarbon (particularly toluene).

The group to introduce the chiral auxiliary group employed here is notparticularly limited so long as it is usually used, and may beN,N-dimethyl-N′—[(S/R)-2-(3,3-dimethyl-1-methoxybutyl)]formamidine,N,N-dimethyl-N′—[(S/R)-2-(3-methyl-1-methoxybutyl)]formamidine orN,N-dimethyl-N′—[(S/R)-2-(3-methyl-1-methoxypentyl)]formamidine, and ispreferablyN,N-dimethyl-N′—[(S)-2-(3,3-dimethyl-1-methoxybutyl)]formamidine orN,N-dimethyl-N′—[(R)-2-(3,3-dimethyl-1-methoxybutyl)]formamidine.

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from 50° C. to 200° C.,preferably from 100° C. to 150° C.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc., but it is usually from one hour to72 hours, preferably from 12 hours to 48 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by pouring the reaction mixture into an aqueous solution suchas a cooled saturated aqueous ammonium chloride solution, adding asolvent immiscible with water (for example, benzene, ether, ethylacetate, etc.) to extract the desired compound, washing the extractedorganic layer with water, drying with anhydrous magnesium sulfate or thelike, and evaporating the solvent. The thus obtained desired compoundcan be further purified, if necessary, according to conventionalmethods, for example, recrystallization, reprecipitation orchromatography.

(Reaction J-1b)

The solvent to be employed here may be an aliphatic hydrocarbon such ashexane, heptane, ligroin or petroleum ether; an aromatic hydrocarbonsuch as benzene, toluene or xylene; or an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, and is preferably an ether(particularly the tetrahydrofuran).

The reagent employed here is a 2-halogeno-1-hydroxyethyl silyl ether,preferably 2-bromo-1-hydroxyethyl-t-butyldimethylsilyl ether.

The base employed here may be an organometal base such as butyl lithium,lithium diisopropylamide or lithium bis(trimethylsilyl)amide, and ispreferably butyl lithium.

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from −90° C. to 0° C.,preferably from −78° C. to −20° C.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc., but it is usually from 5 minutes to12 hours, preferably from 30 minutes to 3 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, the desired compound is obtained by adding methanol andthen evaporating the solvent. The thus obtained desired compound can befurther purified, if necessary, according to conventional methods, forexample, recrystallization, reprecipitation or chromatography.

(Reaction J-1c)

The solvent to be employed here may be an ether such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether; or an alcohol such as methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol,isoamyl alcohol, diethylene glycol, glycerine, octanol, cyclohexanol ormethyl cellosolve, and is preferably an alcohol (particularly ethanol).

The acid to be employed here is not particularly limited so long as itis used in usual reactions as an acid catalyst, and may preferably be anorganic acid such as acetic acid, formic acid, oxalic acid,methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,trifluoroacetic acid or trifluoromethanesulfonic acid, and is preferablyacetic acid.

The reagent employed here is hydrazine, preferably hydrazinemonohydrate.

The reaction temperature varies depending on the solvent, startingcompound, reagent, etc., but it is usually from −20° C. to 50° C.,preferably from 0° C. to 25° C.

The reaction time varies depending on the solvent, starting compound,reagent, reaction temperature, etc., but it is usually from 30 minutesto 24 hours, preferably from one hour to 12 hours.

After the reaction, the desired compound of the present reaction iscollected from the reaction mixture according to conventional methods.For example, after completion of the reaction, the desired compound isobtained by pouring the reaction mixture into an aqueous solution suchas a cooled saturated aqueous ammonium chloride solution, adding asolvent immiscible with water (for example, benzene, ether, ethylacetate, etc.) to extract the desired compound, washing the extractedorganic layer with water, drying with anhydrous magnesium sulfate or thelike and evaporating the solvent. The thus obtained desired compound canbe further purified, if necessary, according to conventional methods,for example, recrystallization, reprecipitation or chromatography.

The optical purity of the desired compound can be measured byconventional methods, for example, analysis by chiral HPLC or the like.

The compounds of the present invention (I) or pharmacologicallyacceptable salts thereof exert both acetylcholinesterase inhibitoryactivity and serotonin re-uptake inhibitory activity. In addition, thecompounds of the present invention (I) exhibit excellentpharmacodynamics, such as absorption, distribution, and eliminationhalf-life from the blood stream, and their toxicity to organs such asthe liver and kidney are low. Thus the compounds of the presentinvention (I) are useful as remedies and particularly they are useful asprophylactic or therapeutic agents for various neurological disorders.

In cases where the compounds of the present invention are used asprophylactic or therapeutic agents for the disorders described above,the compounds expressed by the general formula (I) described above orpharmacologically acceptable salts or esters thereof may be orallyadministered in formulations such as tablets, capsules, granules,powders, or syrups, or non-orally administered in formulations such asinjections, suppositories, patches, or formulations for externalapplication, by optionally mixing with a pharmacologically acceptablediluent and excipient, i.e., carrier, etc.

Preparations are prepared by conventionally known methods usingadditives such as excipients (for instance, organic excipients includingsugar derivatives such as lactose, sucrose, glucose, mannitol andsorbitol; starch derivatives such as corn starch, potato starch,α-starch and dextrin; cellulose derivatives such as crystallinecellulose; gum Arabic; dextran; pullulan; and inorganic excipientsincluding silicate derivatives such as light anhydrous silicic acid,synthetic aluminum silicate, calcium silicate and magnesiumaluminometasilicate; phosphates such as calcium hydrogenphosphate;carbonates such as calcium carbonate; and sulfates such as calciumsulfate), lubricants (for instance, stearic acid, metal salts of stearicacid such as calcium stearate and magnesium stearate; talc; colloidalsilica; waxes such as beeswax and spermaceti; boric acid; adipic acid;sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate;DL-leucine; laurylsulphates such as sodium lauryl sulfate and magnesiumlauryl sulfate; silicates such as silicic anhydride and silicic hydrate;and starch derivatives described above can be listed), binders (forinstance, hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, Macrogol and similar excipients described above),disintegrants (for instance, cellulose derivatives such aslow-substituted hydroxypropylcellulose, carboxymethylcellulose, calciumcarboxymethylcellulose and internally crosslinked-sodiumcarboxymethylcellulose; chemically modified starch/cellulose derivativessuch as carboxymethylstarch, sodium carboxymethylstarch, crosslinkedpolyvinylpyrrolidone;), emulsifiers (for instance, colloidal clay suchas bentonite and veegum; metal hydrates such as magnesium hydroxide andaluminum hydroxide; anionic surfactants such as sodium lauryl sulfateand calcium stearate; cationic surfactants such as benzalkoniumchloride; and non-ionic surfactants such as polyoxyethylenealkyl ethers,polyoxyethylene sorbitan fatty acid esters, and sucrose esters of fattyacids), stabilizers (for instance, para-oxy benzoates such asmethylparaben and propylparaben; alcohols such as chlorobutanol,benzylalcohol and phenylethylalcohol; benzalkonium chloride; phenolssuch as phenol and cresol; thimerosal; dehydroacetic acid; and sorbicacid), flavors (for instance, conventionally employed sweeteners,acidifiers and flavors), and diluents, etc.

The dosage varies depending on the symptoms, age, etc. of the patient(human). For example, in the case of oral administration, it isdesirable to administer 1 mg (preferably 30 mg) as a lower limit and2000 mg (preferably 1500 mg) as an upper limit per one time for an adult(human) and one to six times a day depending on the symptoms. In thecase of intravenous administration, it is desirable to administer 0.5 mg(preferably 5 mg) as a lower limit and 500 mg (preferably 250 mg) as anupper limit per one time for an adult (human) and one to six times a daydepending on the symptoms.

The above dosage ranges are based on a human adult. The dosage range formammals who differ in weight from a human adult would be proportional tothe respective average weight of a human adult and a non-human mammal.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 13-[1-Methylamino-3-[(4-trifluoromethyl)phenyl]propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-14)(a) 3-Acetylphenyl dimethylcarbamate

Tetrahydrofuran (100 ml) was added to sodium hydride (1.94 g, 45 mmol)under an atmosphere of nitrogen. To the suspension was added atetrahydrofuran solution of 1-(3-hydroxyphenyl)ethanone (5.05 g, 37mmol) in an ice bath. After stirring the mixture for 15 minutesdimethylcarbamyl chloride (1.7 ml, 19 mmol) was added dropwise into themixture and the resulting mixture was stirred at room temperature for 4hours. Saturated aqueous sodium chloride solution was added to thereaction mixture. The resulting mixture was extracted with ethylacetate. The organic layer was washed with water and saturated sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column to afford the desired compound(6.54 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.60 (3H, s), 3.03 (3H, s), 3.12 (3H, s),7.34 (1H, d, J=7.9 Hz), 7.46 (1H, t, J=7.9 Hz), 7.70 (1H, s), 7.79 (1H,d, J=7.9 Hz).

(b) 3-[3-(4-Trifluoromethyl)phenyl]acryloyl)phenyl dimethylcarbamate

3-Acetylphenyl dimethylcarbamate (1.30 g, 6.3 mmol) obtained fromExample 1a and 4-(trifluoromethyl)benzaldehyde (1.25 g, 6.9 mmol) weredissolved in ethanol (35 ml). To the ethanol solution was addedpotassium hydroxide (42 mg, 0.63 mmol) and the resulting mixture wasstirred at room temperature for 3 hours. Water was added to the reactionmixture and the aqueous layer was extracted with ether. The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column to afford the desired compound (1.74 g).

¹H-NMR (400 MHz, CDCl₃) δ: 3.04 (3H, s), 3.14 (3H, s), 7.38 (1H, dd,J=8.1 Hz, 1.4 Hz), 7.49-7.57 (2H, m), 7.68 (2H, d, J=8.5 Hz), 7.73-7.77(3H, m), 7.82 (1H, d, J=13.8 Hz), 7.86 (1H, d, J=7.2 Hz).

(c) 3-[3-[(4-Trifluoromethyl)phenyl]propionyl]phenyl dimethylcarbamate

3-[3-(4-Trifluoromethyl)phenyl]acryloyl]phenyl dimethylcarbamate (1.71g, 5.2 mmol) obtained from Example 1b was dissolved in ethyl acetate (50ml). To the solution was added 5% palladium on charcoal (40 mg) and theresulting mixture was stirred under an atmosphere of hydrogen at roomtemperature for 2 hours. The catalyst was removed by filtration and thefiltrate was concentrated under reduced pressure to afford the crudedesired product which was used in next step reaction withoutpurification.

(d) 3-[1-Hydroxy-3-[(4-trifluoromethyl]phenyl]propyl]phenyldimethylcarbamate

The crude product of 3-[3-[(4-trifluoromethyl)phenyl]propionyl]phenyldimethylcarbamate obtained from Example 1c was dissolved in methanol (60ml). To the solution was slowly added sodium borohydride (216 mg, 5.7mmol) in an ice bath and the resulting mixture was stirred for 1 hour.Water was added to the reaction mixture and the methanol was evaporatedunder reduced pressure and the aqueous residue was extracted with ethylacetate. The organic layer was washed with water and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column to afford the desired compound(1.63 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.96-2.15 (2H, m), 2.62-2.84 (2H, m),3.00 (3H, s), 3.10 (3H, s), 4.65 (1H, dd, J=7.5 Hz, 5.4 Hz), 7.02 (1H,d, J=8.4 Hz), 7.11 (1H, s), 7.15 (1H, d, J=7.7 Hz), 7.26-7.35 (3H, m),7.52 (1H, d, J=8.1 Hz)

(e) 3-[1-Bromo-3-[(4-trifluoromethyl)phenyl]propyl]phenyldimethylcarbamate

3-[1-Hydroxy-3-[(4-trifluoromethyl)phenyl]propyl]phenyldimethylcarbamate (372 mg, 1.1 mmol) obtained from Example 1d andtriphenylphosphine (349 mg, 1.3 mmol) were dissolved in dichloromethaneunder an atmosphere of nitrogen. To the solution was added carbontetrabromide (441 mg, 1.3 mmol) in an ice bath and the mixture wasstirred for 20 minutes. The reaction mixture was concentrated underreduced pressure to afford the crude desired product which was used innext step reaction without purification.

(f) 3-[1-Methylamino-3-[(4-trifluoromethyl)phenyl]propyl]phenyldimethylcarbamate hydrochloride

A 40% ethylamine solution in methanol (5 ml) was added to the crudeproduct of 3-[1-bromo-3-[(4-trifluoromethyl)phenyl]propyl]phenyldimethylcarbamate obtained from Example 1d and the mixture was stirredovernight. The reaction mixture was concentrated under reduced pressureand the residue was partitioned between saturated aqueous sodiumhydrogencarbonate solution and ethyl acetate. The organic layer waswashed with water and saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn to give3-[1-methylamino-3-[(4-trifluoromethyl)phenyl]propyl]phenyldimethylcarbamate (209 mg). The product was treated with 1N hydrogenchloride/ethyl acetate solution to afford the title compound as anamorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.39 (3H, s), 2.51-2.61 (3H, m),2.78-2.81 (1H, m), 3.02 (3H, s), 3.12 (3H, s), 3.85 (1H, br s),7.19-7.24 (4H, m), 7.45-7.49 (4H, m), 9.90 (1H, br s), 10.30 (1H, br s).

EXAMPLE 2 3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-15)

4-Methoxybenzaldehyde was treated using similar procedures to thosedescribed in Example 1 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.39 (3H, s), 2.34-2.52 (3H, m),2.70-2.76 (1H, m), 3.02 (3H, s), 3.12 (3H, s), 3.74 (3H, s), 3.84 (1H,br s), 6.77 (2H, d, J=8.6 Hz), 7.03 (2H, d, J=8.6 Hz), 7.21 (1H, dd,J=6.4 Hz, 2.5 Hz), 7.23 (1H, s), 7.43-7.48 (2H, m), 9.83 (1H, br s),10.20 (1H, br s).

EXAMPLE 3 3-[1-Dimethylamino-3-(4-methoxyphenyl)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-16)

Formic acid (10 ml) and 35% aqueous formaldehyde solution (10 ml) wereadded to 3-[3-(4-methoxyphenyl)-1-methylaminopropyl]phenyldimethylcarbamate (500 mg, 1.4 mmol) obtained from Example 2 and themixture was stirred at 90° C. for 2 hours. After cooling the reactionmixture to room temperature the mixture was neutralized with 1N aqueoussodium hydroxide solution. The neutralized mixture was extracted withether and the organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column using ethyl acetate:methanol=80:20as the eluent to give3-[1-dimethylamino-3-(4-methoxyphenyl)propyl]phenyl dimethylcarbamate.The product was treated with 1N hydrogen chloride/ethyl acetate solutionto afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.33-2.39 (1H, m), 2.44-2.57 (2H, m),2.60 (3H, br s), 2.66 (3H, br s), 2.74-2.81 (1H, m), 3.03 (3H, s), 3.14(3H, s), 3.78 (3H, s), 3.95-3.99 (1H, m), 6.81 (2H, d, J=8.6 Hz), 7.02(2H, d, J=8.6 Hz), 7.21 (1H, s), 7.25-7.31 (2H, m), 7.50 (2H, t, J=7.9Hz).

EXAMPLE 4 3-[3-(3,4-Dimethoxyphenyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-17)

3,4-Dimethoxybenzaldehyde was treated using similar procedures to thosedescribed in Example 1 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.39 (3H, s), 2.33-2.60 (3H, m),2.78-2.83 (1H, m), 3.01 (3H, s), 3.11 (3H, s), 3.82 (3H, s), 3.83 (1H,br s), 3.85 (3H, s), 6.65-6.76 (3H, m), 7.20-7.22 (2H, m), 7.45-7.47(2H, m), 9.88 (1H, br s), 10.20 (1H, br s).

EXAMPLE 5 3-(3-Benzo[1,3]dioxol-5-yl-1-methylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-18)

Benzo[1,3]dioxol-5-carboaldehyde was treated using similar procedures tothose described in Example 1 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.40 (3H, s), 2.32-2.50 (3H, m),2.67-2.71 (1H, m), 3.06 (3H, s), 3.12 (3H, s), 3.87 (1H, br s), 5.87(2H, s), 6.55 (1H, d, J=7.9 Hz), 6.61 (1H, s), 6.66 (1H, d, J=7.9 Hz),7.19-7.25 (1H, m), 7.29 (1H, s), 7.44-7.48 (2H, m), 9.84 (1H, br s),10.18 (1H, br s).

EXAMPLE 6 3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenylethylcarbamate hydrochloride (Exemplification Compound Number 2-3) (a)t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methylcarbamate

3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyl dimethylcarbamate (342mg, 1.0 mmol) obtained from Example 2 was dissolved in tetrahydrofuran(5 ml) under an atmosphere of nitrogen and di-tert-butyl dicarbonate(262 mg, 1.2 mmol) was added to the solution. The mixture was stirred atroom temperature overnight. After evaporation of the solvent of thereaction mixture under reduced pressure, the residue was purified bychromatography on a silica gel column using hexane:ethyl acetate=80:20as the eluent to afford the desired compound (420 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.54 (9H, s), 2.11-2.26 (2H, m), 2.66(5H, br s), 3.05 (3H, s), 3.14 (3H, s), 3.85 (3H, s), 5.26 (0.5H, br s),5.55 (0.5H, br s), 6.89 (2H, d, J=8.6 Hz), 7.06-7.15 (2H, m), 7.18 (2H,d, J=8.6 Hz), 7.36 (1H, t, J=8.1 Hz).

(b) t-ButylN-[1-(3-hydroxyphenyl)-3-(4-methoxyphenyl)propyl]-N-methylcarbamate

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methylcarbamate(300 mg, 0.68 mmol) obtained from Example 2a was dissolved in methanol(3 ml) and 1N aqueous lithium hydroxide solution (3 ml) was added to thesolution. The mixture was stirred at room temperature for 3 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with water and saturated aqueous sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column using hexane:ethyl acetate=80:20 as the eluent to afford thedesired compound (245 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.50 (9H, s), 2.10-2.22 (2H, m), 2.64(5H, br s), 3.80 (3H, s), 5,23 (0.5H, br s), 5.50 (0.5H, br s), 6.83(2H, d, J=8.6 Hz), 7.01-7.12 (2H, m), 7.15 (2H, d, J=8.6 Hz), 7.31 (1H,t, J=8.0 Hz).

(c) t-ButylN-[1-[(3-ethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methylcarbamate

t-ButylN-[1-(3-hydroxyphenyl)-3-(4-methoxyphenyl)propyl]-N-methylcarbamate (250mg, 0.67 mmol) obtained from Example 6b was dissolved in tetrahydrofuran(2 ml) under an atmosphere of nitrogen, and triethylamine (0.16 ml, 1.3mmol) and ethyl isocyanate (0.11 ml, 1.3 mmol) were sequentially addedto the solution. The resulting mixture was stirred at room temperaturefor 1 hour and concentrated under reduced pressure. The residue waspurified by chromatography on a silica gel column using hexane:ethylacetate=90:10 as the eluent to give the desired compound (198 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.21 (3H, t, J=7.3 Hz), 1.48 (9H, s),2.06-2.19 (2H, m), 2.60 (5H, br s), 3.27-3.38 (2H, m), 3.79 (3H, s),5.00 (1H, br s), 5.20 (0.5H, br s), 5.45 (0.5H, br s), 6.84 (2H, d,J=8.6 Hz), 7.02-7.11 (2H, m), 7.13 (2H, d, J=8.6 Hz), 7.30 (1H, t, J=8.0Hz).

(d) 3-[3-(4-Methoxyphenyl)-1-methylaminopropyl]phenyl ethylcarbamatehydrochloride

t-ButylN-[1-[(3-ethylcarbamoyloxy)phenyl]-3-(4-methoxyphenyl)propyl]-N-methylcarbamate(198 mg, 0.45 mmol) obtained from Example 6c was dissolved in ethylacetate (3 ml) and 4N hydrogen chloride/ethyl acetate solution (1 ml)was added to the solution. The mixture was stirred at room temperatureovernight and concentrated under reduced pressure. The residue waspartitioned between saturated aqueous sodium hydrogencarbonate solutionand ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by chromatography on a silica gel column using ethyl acetatemethanol=80:20 as the eluent to give3-[3-(4-methoxyphenyl)-1-methylaminopropyl]phenyl ethylcarbamate (133mg). The product was treated with 1N hydrogen chloride/ethyl acetatesolution to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.23 (3H, t, J=7.3 Hz), 2.38 (3H, s),2.33-2.52 (3H, m), 2.70-2.75 (1H, m), 3.28-3.36 (2H, m), 3.74 (3H, s),3.84. (1H, br s), 5.16 (1H, t, J=5.7 Hz), 6.77 (2H, d, J=8.6 Hz), 7.02(2H, d, J=8.6 Hz), 7.23 (1H, d, J=8.1 Hz), 7.26 (1H, s), 7.39-7.47 (2H,m), 9.80 (1H, br s), 10.17 (1H, br s).

EXAMPLE 7 3-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-85)(a) 3-(3-Hydroxyphenyl)-3-methylaminopropionic acid

3-Hydroxybenzaldehyde (25.7 g, 210 mmol) was dissolved in ethanol (70ml), and malonic acid (25.7 g) and the acetic acid salt of methylamine(38.6 g) were added to the solution. The resulting mixture was heatedunder reflux for 3 hours. Crystals which precipitated in the reactionmixture were collected by filtration to afford the desired compound(24.1 g).

¹H-NMR (400 MHz, DMSO-d₆) δ: 2.23 (3H, s), 2.30(1H, dd, J=15.5, 4.1 Hz),2.42-2.48(1H, m), 3.89-3.92(1H, m), 6.70(1H, dd, J=7.8, 1.7 Hz),6.78-6.81(2H, m), 7.15(1H, t, J=7.8 Hz), 9.50(1H, brs).

(b) Ethyl 3-(3-hydroxyphenyl)-3-methylaminopropionate

3-(3-Hydroxyphenyl)-3-methylaminopropionic acid (24.1 g) obtained fromExample 7a was dissolved in ethanol (200 ml), and concentrated sulfuricacid (10 ml) was added dropwise to the solution. The resulting mixturewas heated under reflux for 8 hours. The reaction mixture wasneutralized with saturated aqueous sodium hydrogencarbonate solution andthe solvent was removed under reduced pressure. The residual aqueoussolution was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and concentrated under reduced pressureto afford the desired compound which was used in next step reactionwithout further purification.

(c) Ethyl3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(3-hydroxyphenyl)propionate

The crude product of ethyl 3-(3-hydroxyphenyl)-3-methylaminopropionateobtained from Example 7b was dissolved in tetrahydrofuran (200 ml) underan atmosphere of nitrogen and di-tert-butyl dicarbonate (32 g, 150 mmol)was added to the solution. The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureand purified by chromatography on a silica gel column using hexane:ethylacetate=70:30 as the eluent to afford the desired compound (37 g).

¹H-NMR (400 MHz, CDCl₃) δ: 1.24(3H, t, J=7.1 Hz), 1.47(9H, s), 2.64(3H,brs), 2.84-2.96(2H, m), 4.10-4.16(2H, m), 5.64(1/2H, brs), 5.82(1/2H,brs), 6.74-6.76(2H, m), 6.8(1H, d, J=7.7 Hz), 7.20(1H, t, J=8.1 Hz).

(d) Ethyl3-[N-(t-butoxycarbonyl)-N-methylamino]-3-[(3-dimethylcarbamoyloxy)phenyl]propionate

Tetrahydrofuran (100 ml) was added to sodium hydride (1.01 g, 23 mmol)under an atmosphere of nitrogen and to the mixture was added a solutionof ethyl3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(3-hydroxyphenyl)propionate(5.00 g, 16 mmol) obtained from Example 7c in tetrahydrofuran in an icebath. After stirring the resulting mixture for 20 minutes,dimethylcarbamyl chloride (1.7 ml, 19 mmol) was added dropwise and theresulting mixture was stirred at room temperature for 1 hour. Thereaction mixture was partitioned between saturated aqueous sodiumchloride solution and ethyl acetate. The organic layer was washed withwater and saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column usinghexane:ethyl acetate=60:40 to afford the desired compound (4.85 g).

¹H-NMR (400 MHz, CDCl₃) δ: 1.24(3H, t, J=7.1 Hz), 1.47(9H, s), 2.67(3H,brs), 2.90-2.93(2H, m), 3.01(3H, s), 3.10(3H, s), 4.11-4.15(2H, m),5.67(1/2H, brs), 5.85(1/2H, brs), 6.99(1H, s), 7.05(1H, dd, J=7.9, 2.0Hz), 7.10(1H, brs), 7.32(1H, t, d=7.9 Hz).

(e) t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate

Tetrahydrofuran (100 ml) was added to lithium aluminum hydride (770 mg,20 mmol) under an atmosphere of nitrogen, and to the mixture was added atetrahydrofuran solution of ethyl3-[N-(t-butoxycarbonyl)-N-methylamino]-3-[(3-dimethylcarbamoyloxy)phenyl]propionate(4.01 g 10 mmol) obtained from Example 7d at −78° C. After stirring themixture for 20 minutes, the mixture was slowly warmed to 0° C. and thenstirred for 30 minutes. To the reaction mixture was added sequentiallywater (0.8 ml), 15% aqueous sodium hydroxide solution (0.8 ml) and water(0.8 ml). The resulting mixture was stirred at room temperature for 30minutes. After addition of anhydrous magnesium sulfate to the mixture,the resulting mixture was filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by chromatography on asilica gel column using hexane:ethyl acetate=20:80 as the eluent toafford the desired compound (2.40 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.51(9H, s), 1.92-1.97(1H, m),2.14-2.21(1H, m), 2.46(3H, s), 3.02(3H, s), 3.11(3H, s), 3.48-3.54(1H,m), 3.58-3.62(1H, m), 3.75(1H, brs), 5.57-5.60(1H, m), 7.04-7.06(2H, m),7.13-7.15(1H, m), 7.34(1H, t, J=8.2 Hz).

(f) t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-[(4-trifluoromethyl)phenoxy]propyl]-N-methylcarbamate

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate(200 mg, 0.56 mmol) obtained from Example 7e was dissolved intetrahydrofuran (2 ml) under an atmosphere of nitrogen. Triethylamine(0.14 ml, 1.0 mmol) and methanesulfonyl chloride (0.06 ml, 0.68 mmol)was sequentially added to the solution in an ice bath. The mixture wasstirred at room temperature for 30 minutes. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate and concentrated under reduced pressure to give amethanesulfonate. On the other hand N,N-dimethylformamide (2 ml) wasadded to sodium hydride (30 mg, 0.63 mmol) under an atmosphere ofnitrogen. A solution of 4-(trifluoromethyl)phenol (110 mg, 0.63 mmol) inN,N-dimethylformamide was added to the suspension of sodium hydride inan ice bath and the mixture was stirred for 30 minutes. To this reactionmixture was added a solution of the methanesulfonate obtained above inN,N-dimethylformamide and the mixture was stirred at room temperatureovernight. The reaction mixture was partitioned between water and ether.The organic layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column using hexane:ethyl acetate=50:50 as the eluent to afford thedesired compound (243 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.39(9H, s), 2.34-2.47(2H, m), 2.62(3H,s), 3.02(3H, s), 3.11(3H, s), 4.07(2H, brs), 5.57(1H, brs), 6.95(2H, d,J=8.6 Hz), 7.05-7.06(2H, m), 7.14-7.16(1H, m), 7.34(1H, t, J=8.1 Hz),7.54(2H, d, J=8.6 Hz).

(g) 3-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate hydrochloride

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-[(4-trifluoromethyl)phenoxy]propyl]-N-methylcarbamateobtained from Example 7f was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54 (3H, s), 2.58-2.65 (1H, m), 2.98(3H, s), 2.98-3.07 (1H, m), 3.07 (3H, s), 3.68-3.72 (1H, m), 4.01-4.05(1H, m), 4.31-4.34 (1H, m), 6.86 (2H, d, J=8.7 Hz), 7.18 (1H, d, J=7.4Hz), 7.31 (1H, s), 7.42-7.50 (4H, m).

MS (FAB) m/z: 397 (M+H)⁺.

EXAMPLE 8 3-[3-(4-Methoxyphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-86)

4-Methoxyphenol was treated using similar procedures to those describedin Example 7f and 7g to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.50-2.57 (1H, m), 2.53 (3H, s),2.93-3.01 (1H, m), 2.99 (3H, s), 3.08 (3H, s), 3.57-3.61 (1H, m), 3.73(3H, s), 3.91-3.94 (1H, m), 4.32-4.35 (1H, m), 6.73-6.78 (4H, m), 7.18(1H, d, J=7.8 Hz), 7.34 (1H, s), 7.41-7.49 (2H, m).

MS (EI) m/z: 358 (M)⁺.

EXAMPLE 9 3-(1-Methylamino-3-p-toluyloxypropyl)phenyl dimethylcarbamatehydrochloride (Exemplification Compound Number 2-82)

4-Methylphenol was treated using similar procedures to those describedin Example 7f and 7g to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.24 (3H, s), 2.53 (3H, s), 2.53-2.58(1H, m), 2.92-2.99 (1H, m), 2.99 (3H, s), 3.08 (3H, s), 3.56-3.62 (1H,m), 3.91-3.94 (1H, m), 4.32-4.36 (1H, m), 6.69 (2H, d, J=8.4 Hz), 7.02(2H, d, J=8.4 Hz), 7.18 (1H, d, J=7.9 Hz), 7.34 (1H, s), 7.39-7.47 (2H,m).

MS (FAB) m/z: 343 (M+H)⁺.

EXAMPLE 10 3-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-78)

4-Chlorophenol was treated using similar procedures to those describedin Example 7f and 7g to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.53-2.58 (1H, m),2.94-3.01 (1H, m), 2.99 (3H, s), 3.08 (3H, s), 3.58-3.63 (1H, m),3.94-3.96 (1H, m), 4.30-4.33 (1H, m), 6.73 (2H, d, J=9.0 Hz), 7.15-7.19(3H, m), 7.31 (1H, s), 7.31-7.45 (2H, m).

MS (FAB) m/z: 363 (M+H)⁺.

EXAMPLE 11 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-75)(a) t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methylcarbamate

4-Fluorophenol was treated using a similar procedure to that describedin Example 7f to afford the desired compound.

¹H-NMR400 MHz, CDCl₃) δ: 1.40(9H, s), 2.30-2.42(2H, m), 2.61(3H, s),3.02(3H, s), 3.11(3H, s), 3.94-3.98(2H, m), 5.56(1H, brs), 6.80-6.84(2H,m), 6.96(2H, t, J=8.6 Hz), 7.04-7.05(2H, m), 7.13-7.15(1H, m), 7.34(1H,t, J=8.3 Hz).

(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methylcarbamateobtained from Example 11a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.53-2.59 (1H, m),2.94-3.05 (1H, m), 2.99 (3H, s), 3.08 (3H, s), 3.59-3.63 (1H, m),3.92-3.96 (1H, m), 4.31-4.34 (1H, m), 6.73-6.78 (2H, m), 6.91 (2H, t,J=8.6 Hz), 7.18 (1H, d, J=6.7 Hz), 7.32 (1H, s), 7.42-7.47 (2H, m).

MS (FAB) m/z: 347 (M+H)⁺.

EXAMPLE 12 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenylethylcarbamate hydrochloride (Exemplification Compound Number 2-2) (a)t-ButylN-[3-[(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methylcarbamateobtained from Example 11a was treated using a similar procedure to thatdescribed in Example 6b to afford the desired compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41 (9H, br s), 2.30-2.43 (2H, m), 3.97(2H, br s), 5.52 (1H, br s), 5.98 (0.5H, br s), 6.40 (0.5H, br s),6.76-6.86 (5H, m), 6.95 (1H, t, J=8.4 Hz), 7.21 (1H, t, J=7.8 Hz).

(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl ethylcarbamatehydrochloride

t-ButylN-[3-[(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamateobtained from Example 12a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.88 (3H, t, J=7.3 Hz), 2.53 (3H, s),2.52-2.59 (1H, m), 2.90-3.00 (1H, m), 3.25-3.31 (2H, m), 3.57-3.61 (1H,m), 3.92-3.95 (1H, m), 4.30-4.34 (1H, m), 5.04-5.09 (1H, m), 6.73 (2H,dd, J=9.0 Hz, 4.3 Hz), 6.91 (2H, t, J=9.0 Hz), 7.21-7.24 (1H, m), 7.36(1H, s), 7.41-7.44 (2H, m), 9.88 (1H, br s), 10.22 (1H, br s).

MS(FAB) m/z: 347 (M+H)⁺.

EXAMPLE 13 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl acetatehydrochloride (Exemplification Compound Number 2-4) (a)3-[1-(N-t-Butoxycarbonyl-N-methylamino)-3-(4-fluorophenoxy)propyl]phenylacetate

t-ButylN-[3-[(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate(100 mg, 0.27 mmol) obtained from Example 12a was dissolved indichloromethane (1 ml) under an atmosphere of nitrogen, andtriethylamine (0.045 ml, 0.32 mmol) and acetic anhydride (0.030 ml, 0.32mmol) were added to the solution. The resulting mixture was stirred atroom temperature overnight. The reaction mixture was partitioned betweenwater and dichloromethane. The organic layer was washed with water andsaturated aqueous sodium chloride solution, dried over magnesium sulfateand concentrated under reduced pressure. The residue was purified bychromatography on a silica gel column using hexane:ethyl acetate=80:20to 75:25 as the eluent to afford the desired compound (98.7 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40 (9H, s), 2.40 (3H, s), 2.34-2.57(2H, m), 2.62 (3H, s), 3.97-3.99 (2H, m), 5.54-5.87 (1H, m), 6.82 (2H,dd, J=9.1 Hz, 4.3 Hz), 6.94-6.83 (3H, m), 7.02 (1H, d, J=6.2 Hz), 7.18(1H, d, J=7.1 Hz), 7.36 (1H, t, J=8.1 Hz).

(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl acetatehydrochloride

3-[1-(N-t-Butoxycarbonyl-N-methylamino)-3-(4-fluorophenoxy)propyl]phenylacetate obtained from Example 13a was treated using a similar procedureto that described in Example 6d to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.28 (3H, s), 2.53 (3H, s), 2.51-2.60(1H, m), 2.95-3.01 (1H, m), 3.56-3.61 (1H, m), 3.92-3.96 (1H, m), 4.35(1H, br s), 6.72 (2H, dd, J=8.8 Hz, 4.3 Hz), 6.91 (2H, t, J=8.8 Hz),7.16 (1H, d, J=7.7 Hz), 7.34 (1H, s), 7.43-7.50 (2H, m), 9.97 (1H, brs), 10.30 (1H, br s).

MS(FAB) m/z: 318 (M+H)⁺.

EXAMPLE 14 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl2,2-dimethylpropionate hydrochloride (Exemplification Compound Number2-5)

2,2-Dimethylpropionyl chloride was treated using similar procedures tothose described in Example 13 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.33 (s, 9 H), 2.54 (3H, s), 2.48-2.57(1H, m), 2.96-3.01 (1H, m), 3.55-3.59 (1H, m), 3.91-3.96 (1H, m),4.32-4.36 (1H, m), 6.73 (2H, dd, J=9.1 Hz, 4.3 Hz), 6.91 (2H, t, J=9.1Hz), 7.11 (1H, d, J=7.1 Hz), 7.30 (1H, s), 7.43-7.50 (2H, m), 9.98 (1H,br s), 10.38 (1H, br s).

MS(FAB) m/z: 360 (M+H)⁺.

EXAMPLE 15 3-[3-(4-Chlorophenyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-13)

4-Chlorobenzaldehyde was treated using similar procedures to thosedescribed in Example 1 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.39 (3H, s), 2.39-2.56 (3H, m), 2.75(1H, br s), 3.02 (3H, s), 3.12 (3H, s), 3.83 (1H, br s), 7.05 (2H, d,J=8.3 Hz), 7.20 (2H, d, J=8.3 Hz), 7.17-7.23 (2H, m), 7.40-7.49 (2H, m),9.85 (1H, br s), 10.25 (1H, br s).

MS(FAB) m/z: 347 (M+H)⁺.

EXAMPLE 16 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-78)(a) Ethyl3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propionate

4-Hydroxybenzaldehyde was treated using similar procedures to thosedescribed in Example from 7a to 7c to afford the desired compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 1.91-1.98 (1H, m),2.13-2.20 (1H, m), 2.43 (3H, s), 3.02 (3H, s), 3.10 (3H, s), 3.48-3.58(2H, m), 3.74(1H, br s), 5.57-5.61 (1H, m), 7.10 (2H, dt, J=8.6, 1.9Hz), 7.28 (2H, d, J=8.6 Hz).

(b) t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate

Ethyl3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propionateobtained from Example 16a was treated using similar procedures to thosedescribed in Example 7d and 7e to afford the desired compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40(9H, s), 2.29-2.44(2H, m), 2.60(3H,s), 3.01(3H, s), 3.10(3H, s), 3.98(2H, br s), 5.56(1H, br s), 6.81(2H,d, J=8.8 Hz), 7.10(2H, d, J=8.5 Hz), 7.22(2H, d, J=8.8 Hz),7.28-7.30(2H, m).

(c) 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-chlorophenol were treated using similarprocedures to those described in Example 7f and 6d to afford the titlecompound as amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, s), 2.51-2.59 (1H, m),2.94-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.55-3.59 (1H, m),3.91-4.13 (1H, m), 4.30-4.34 (1H, m), 6.71 (2H, d, J=9.0 Hz), 7.15-7.19(4H, m), 7.59 (2H, d, J=8.6 Hz).

IR(KBr) v_(max)cm⁻¹: 3430, 2942 2765, 2699, 1725.

MS (FAB) m/z: 363([M+H]⁺), 332, 273, 242, 207.

EXAMPLE 17 4-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-85)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-trifluoromethylphenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.58-2.64 (1H, m),2.99-3.03 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.64-3.68 (1H, m),3.99-4.03 (1H, m), 4.32-4.35 (1H, m), 6.85 (2H, d, J=8.7 Hz), 7.19 (2H,d, J=8.6 Hz), 7.48 (2H, d, J=8.7 Hz), 7.59 (2H, d, J=8.6 Hz).

MS (FAB) m/z: 397 (M+H)⁺.

EXAMPLE 18 4-[3-[(4-Methoxyphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-86)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-methoxyphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, s), 2.51-2.54 (1H, m),2.92-2.97 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.53-3.58 (1H, m), 3.73(3H, s), 3.90-3.92 (1H, m), 4.34-4.36 (1H, m), 6.72-6.81 (4H, m), 7.18(2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz).

MS (FAB) m/z: 359 (M+H)⁺.

EXAMPLE 19 3-[1-Amino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamatehydrochloride (Exemplification Compound Number 2-65) (a) t-Butyl[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]carbamate

Ammonium acetate was treated using similar procedures to those describedin from Example 7a to 7e to afford the desired compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40 (9H, br s) 2.22 (2H, br s), 3.00(3H, s), 3.09 (3H, s), 3.84-3.96 (2H, m), 4.92 (1H, br s), 5.18 (1H, brs), 6.81 (2H, dd, J=8.8 Hz, 4.3 Hz), 6.95 (2H, t, J=8.8 Hz), 7.00-7.05(2H, m), 7.21 (1H, d, J=7.8 Hz), 7.31 (1H, t, J=7.8 Hz).

(b) 3-[1-Amino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamatehydrochloride

t-Butyl[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]carbamateobtained from Example 19a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.35-2.39 (1H, m), 2.69-2.74 (1H, m),2.88 (3H, s), 3.04 (3H, s), 3.64-3.71 (1H, m), 3.91-3.96 (1H, m), 4.53(1H, br s), 6.74 (2H, dd, J=8.9 Hz, 4.3 Hz), 6.90 (2H, t, J=8.9 Hz),7.02 (1H, d, J=8.0 Hz), 7.31-7.39 (3H, m), 8.71 (3H, br s).

EXAMPLE 20 3-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-67)(a) t-ButylN-[1-(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-ethylcarbamate

N,N-Dimethylformamide (2 ml) was added to sodium hydride (12 mg, 0.28mmol) under an atmosphere of nitrogen, and to the mixture was added asolution of t-butyl[1-[(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]carbamate(100 mg, 0.23 mmol) obtained from Example 19a in N,N-dimethylformamidein an ice bath. After stirring the resulting mixture for 20 minutes,ethyl iodide (0.022 ml, 0.28 mmol) was added dropwise thereto and thismixture was stirred at room temperature overnight. The reaction mixturewas partitioned between water and ethyl acetate. The organic layer waswashed with water and saturated aqueous sodium chloride solution, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column usinghexane:ethyl acetate=90:10 to 70:30 as the eluent to afford the desiredcompound (63 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.42 (9H, br s), 2.39-2.47 (2H, m), 3.01(3H, s), 3.02-3.09 (2H, m), 3.10 (3H, s), 3.96-4.05 (2H, m), 5.44 (1H,br s), 6.82 (2H, dd, J=8.9 Hz, 4.3 Hz), 6.96 (2H, t, J=8.9 Hz), 7.04(1H, t, J=7.9 Hz), 7.09 (1H, s), 7.18 (1H, d, J=7.9 Hz), 6.32 (1H, t,J=7.9 Hz).

(b) 3-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-(3-dimethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-ethylcarbamateobtained from Example 20a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorhoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.46 (3H, t, J=7.2 Hz), 2.60-2.65 (1H,m), 2.83-3.00 (2H, m), 2.99 (3H, s), 3.08 (3H, s), 3.06-3.11 (1H, m),3.52-3.57 (1H, m), 3.86-3.90 (1H, m), 4.40 (1H, br s), 6.71 (2H, dd,J=9.0 Hz, 4.3 Hz), 6.90 (2H, t, J=9.0 Hz), 7.18 (1H, d, J=7.8 Hz), 7.37(1H, s), 7.43 (1H, t, J=7.8 Hz), 7.51 (1H, d, J=7.8 Hz), 9.97 (1H, brs), 10.34 (1H, br s).

EXAMPLE 21 3-[3-(4-Fluorophenoxy)-1-propylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-73)

1-Iodopropane was treated using similar procedures to those described inExample 20 to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.90 (3H, t, J=7.4 Hz), 1.90-2.01 (2H,m), 2.60-2.67 (1H, m), 2.72 (2H, t, J=8.1 Hz), 3.00 (3H, s), 3.08 (3H,s), 3.07-3.15 (1H, m), 3.52-3.57 (1H, m), 3.83-3.89 (1H, m), 4.36-4.40(1H, m), 6.70 (2H, dd, J=8.9 Hz, 4.3 Hz), 6.90 (2H, t, J=8.9 Hz), 7.19(1H, d, J=7.9 Hz), 7.37 (1H, s), 7.43 (1H, t, J=7.9 Hz), 7.51 (1H, d,J=7.9 Hz), 9.88 (1H, br s), 10.27 (1H, br s).

EXAMPLE 22 3-[4-(4-Fluorophenyl)-1-methylaminobutyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-25)(a) t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-oxo-propyl]-N-methylcarbamate

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamate(200 mg, 0.57 mmol) was dissolved in dichloromethane (3 ml) under anatmosphere of nitrogen and pyridinium dichromate (320 mg, 0.85 mmol) wasadded to the solution. The resulting mixture was stirred at roomtemperature overnight. After addition of ether to the reaction mixture,the crystals was collected by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column using hexane:ethyl acetate=80:20to 60:40 as the eluent to afford the desired compound (148 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.48 (9H, s), 2.59 (3H, br s), 2.95-3.01(2H, m), 3.02 (3H, s), 3.11 (3H, s), 6.02 (1H, br s), 6.99 (1H, s),7.05-7.08 (2H, m), 7.35 (1H, t, J=7.9 Hz), 9.80 (1H, s).

(b) t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)-3-butenyl]-N-methylcarbamate

Tetrahydrofuran (1 ml) was added to sodium hydride (14 mg, 0.31 mmol)under an atmosphere of nitrogen and a solution of(4-fluorobenzyl)triphenylphosphonium bromide (110 mg, 0.27 mmol) intetrahydrofuran was added to the sodium hydride. The resulting mixturewas stirred for 2 hours and then t-butylN-methy-N-[1-(3-nitrophenyl)-3-oxopropyl]carbamate (72 mg, 0.21 mmol)obtained from Example 22a was added thereto. The resulting mixture wasstirred at room temperature for 3 hours. The reaction mixture waspartitioned between saturated aqueous sodium chloride solution and ethylacetate. The organic layer was washed with water and saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column using hexane:ethyl acetate=90:10to 70:30 to afford the desired compound (80 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41 (4.5H, s), 1.48 (4.5H, s), 2.47-2.90(5H, m), 3.01 (1.5H, s), 3.02 (l.5H, s), 3.10 (1.5H, s), 3.11 (1.5H, s),5.61-6.51 (3H, m), 6.96-7.36 (8H, m).

(c) t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)butyl]-N-methylcarbamate

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)-3-butenyl]-N-methylcarbamate(42 mg, 1.3 mmol) obtained from Example 22b was dissolved in methanol (1ml) and to the solution was added 5% palladium on charcoal (10 mg). Themixture was stirred under an atmosphere of hydrogen at room temperaturefor 1 hour and the reaction mixture was filtered in order to remove thecatalyst. The filtrate was concentrated under reduced pressure and theresidue was purified by chromatography on a silica gel column usinghexane:ethyl acetate=90:10 to 75:25 as the eluent to afford the desiredcompound (40 mg).

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.48 (9H, s), 1.60-1.69 (2H, m), 2.53(3H, br s), 2.59-2.65 (1H, m), 2.69-2.75 (1H, m), 3.01 (3H, s), 3.10(3H, s), 5.23 (0.5H, br s), 5.44 (0.5H, br s), 6.94-7.15 (7H, m), 7.30(1H, t, J=7.9 Hz).

(d) 3-[4-(4-Fluorophenyl)-1-methylaminobutyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-4-(4-fluorophenyl)butyl]-N-methylcarbamateobtained from Example 22c was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.39-1.47 (1H, m), 1.52-1.60 (1H, m),2.18-2.27 (1H, m), 2.41 (3H, s), 2.40-2.62 (3H, m), 3.01 (3H, s), 3.11(3H, s), 3.90 (1H, dd, J=10.5 Hz, 4.4 Hz), 6.90 (2H, t, J=8.6 Hz), 7.02(2H, dd, J=8.6 Hz, 5.5 Hz), 7.19 (1H, d, J=7.3 Hz), 7.22 (1H, s),7.41-7.48 (2H, m), 9.83 (1H, br s), 10.16 (1H, br s).

EXAMPLE 23 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyldiethylcarbamate hydrochloride (Exemplification Compound Number 2-6) (a)t-ButylN-[1-[(3-diethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methylcarbamate

N,N-Dimethylformamide (1 ml) was added to sodium hydride (14 mg, 0.32mmol) under an atmosphere of nitrogen and to the sodium hydride wasadded a solution of t-butylN-[3-(4-fluorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate (100mg, 0.27 mmol) obtained from Example 12a in N,N-dimethylformamide in anice bath. The mixture was stirred for 30 minutes and to this mixture wasadded diethylcarbamyl chloride (0.041 ml, 0.32 mmol). The resultingmixture was stirred for 1 hour and the reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was washed with waterand saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by chromatography on a silica gel column usingmethylenechloride:ethyl acetate=10:90 as the eluent to afford thedesired compound (108 mg).

¹H-NMR (400 MHz, CDCl₃) (400 MHz, CDCl₃) δ ppm: 1.19-1.28(6H, m),1.40(9H, s), 2.31-2.44(2H, m), 2.62(3H, s), 3.37-3.47(4H, m),3.97-3.99(2H, m), 5.56(1H, brs), 6.81-6.84(2H, m), 6.96(2H, t, J=8.6Hz), 7.05-7.11(2H, m), 7.12-7.16(1H, m), 7.34(1H, t, J=8.2 Hz).

(b) 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl diethylcarbamatehydrochloride

t-ButylN-[1-[(3-diethylcarbamoyloxy)phenyl]-3-(4-fluorophenoxy)propyl]-N-methylcarbamateobtained from Example 23a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.20-1.29 (6H, m), 2.55 (3H, s),2.55-2.62 (1H, m), 2.98-3.04 (1H, m), 3.36-3.45 (4H, m), 3.59-3.64 (1H,m), 3.94-3.98 (1H, m), 4.33-4.36 (1H, m), 6.74-6.78 (2H, m), 6.92 (2H,t, J=8.6 Hz), 7.21 (1H, d, J=7.5 Hz), 7.34 (1H, s), 7.43-7.50 (2H, m).

MS (FAB) m/z: 375 (M+H)⁺.

EXAMPLE 24 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyldiisopropylcarbamate hydrochloride (Exemplification Compound Number 2-9)

Diisopropylcarbamyl chloride was treated using similar procedures tothose described in Example 23 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.28 (12H, brs), 2.54 (3H, s), 2.54-2.59(1H, m), 2.95-3.02 (1H, m), 3.57-3.62 (1H, m), 3.92-3.99 (2H, m), 4.05(1H, brs), 4.32-4.35 (1H, m), 6.76-6.78 (2H, m), 6.90 (2H, t, J=8.6 Hz),7.19 (1H, dd, J=7.9 Hz, 1.0 Hz), 7.28 (1H, d, J=1.0 Hz), 7.42 (1H, t,J=7.9 Hz), 7.49 (1H, d, J=7.9 Hz).

MS (FAB) m/z: 403 (M+H)⁺.

EXAMPLE 25 3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenylmorpholin-4-carboxylate hydrochloride (Exemplification Compound Number2-11)

Morpholin-4-carbonyl chloride was treated using similar procedures tothose described in Example 23 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.53-2.59 (1H, m),2.96-2.99 (1H, m), 3.54-3.64 (5H, m), 3.74 (4H, d, J=4.7 Hz), 3.93-3.95(1H, m), 4.31-4.35 (1H, m), 6.72-6.75 (2H, m), 6.91 (2H, t, J=8.7 Hz),7.19 (1H, d, J=6.9 Hz), 7.35 (1H, s), 7.42-7.46 (2H, m)

MS (FAB) m/z: 389 (M+H)⁺.

EXAMPLE 26O-[3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl]dimethylthiocarbamatehydrochloride (Exemplification Compound Number 2-12)

Dimethylthiocarbamyl chloride was treated using similar procedures tothose described in Example 23 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.55 (3H, s), 2.55-2.63 (1H, m),2.99-3.02 (1H, m), 3.33 (3H, s), 3.43 (3H, s), 3.62-3.68 (1H, m),3.91-3.95 (1H, m), 4.33-4.37 (1H, m), 6.72-6.75 (2H, m), 6.90 (2H, t,J=8.7 Hz), 7.11 (1H, d, J=7.8 Hz), 7.26 (1H, s), 7.47 (1H, t, J=7.8 Hz),7.53 (1H, t, J=7.8 Hz).

MS (FAB) m/z: 363 (M+H)⁺.

EXAMPLE 273-[1-Dimethylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-142)

3-[1-Methylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate obtained from Example 7g was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.64 (3H, s), 2.64-2.74 (1H, m), 2.87(3H, s), 2.95-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.64-3.70 (1H,m), 4.04-4.13 (1H, m), 4.29-4.31 (1H, m), 6.81 (2H, d, J=8.5 Hz), 7.22(1H, m), 7.30 (1H, s), 7.38 (1H, d, J=7.7 Hz), 7.43-7.50 (3H, m).

MS (FAB) m/z: 411 (M+H)⁺.

EXAMPLE 28 3-[1-Dimethylamino-3-(4-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-132)

3-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 11b was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.63-2.68 (4H, m), 2.87 (3H, s),2.92-3.01 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.54-3.60 (1H, m),3.95-4.13 (1H, m), 4.28-4.30 (1H, m), 6.67-6.70 (2H, m), 6.91 (2H, t,J=8.6 Hz), 7.23 (1H, d, J=7.8 Hz), 7.32 (1H, s), 7.39 (1H, d, J=7.8 Hz),7.45 (1H, t, J=7.8 Hz).

MS (FAB) m/z: 361 (M+H)⁺.

EXAMPLE 294-[1-Dimethylamino-3-[(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-142)

4-[1-Methylamino-3-(4-trifluoromethyl)phenoxy]propyl]phenyldimethylcarbamate obtained from Example 17 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 2.61 (3H, s), 2.72-2.75 (1H, m), 2.91 (3H,s), 2.96-3.02 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.58-3.63 (1H, m),4.03-4.06 (1H, m), 4.27-4.31 (1H, m), 6.81 (2H, d, J=8.5 Hz), 7.23 (2H,d, J=8.2 Hz), 7.49 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.2 Hz).

MS (FAB) m/z: 411 (M+H)⁺.

EXAMPLE 30 4-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-75)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-fluorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.46-2.60 (1H, m), 2.51 (3H, s),2.92-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.53-3.59 (1H, m),3.90-3.94 (1H, m), 4.33-4.34 (1H, m), 6.70-6.73 (2H, m), 6.91 (2H, t,J=8.7 Hz), 7.18 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.6 Hz).

MS (FAB) m/z: 347 (M+H)⁺.

EXAMPLE 31 4-[1-Dimethylamino-3-(4-trifluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-132)

4-[3-(4-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 30 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54-2.69 (1H, m), 2.60 (3H, d, J=4.0Hz), 2.85-2.96 (1H, m), 2.91 (3H, d, J=4.0 Hz), 3.02 (3H, s), 3.11 (3H,s), 3.47-3.52 (1H, m), 3.94-3.96 (1H, m), 4.27-4.30 (1H, m), 6.66-6.70(2H, m), 6.92 (2H, t, J=8.6 Hz), 7.23 (2H, d, J=8.1 Hz), 7.58 (2H, d,J=8.1 Hz).

MS (FAB) m/z: 361 (M+H)⁺.

EXAMPLE 32 3-[3-(4-Fluorophenyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-1)

4-Fluorobenzaldehyde was treated using similar procedures to thosedescribed in Example 1 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.39 (3H, s), 2.34-2.54 (3H, m),2.70-2.78 (1H, m), 3.02 (3H, s), 3.12 (3H, s), 3.80-3.87 (1H, m), 6.91(2H, t, J=8.4 Hz), 7.07 (2H, dd, J=8.4 Hz, 5.6 Hz), 7.17-7.24 (2H, m),7.40-7.49 (2H, m).

MS(EI) m/z: 331 (M+H)⁺.

EXAMPLE 33 4-[3-(4-Fluorophenyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-1)

4-Acetylphenol and 4-fluorobenzaldehyde were treated using similarprocedures to those described in Example 1 to afford the title compoundas an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.37 (3H, s), 2.33-2.54 (3H, m),2.69-2.78 (1H, m), 3.03 (3H, s), 3.12 (3H, s), 3.85 (1H, br s),6.88-6.96 (2H, m), 7.01-7.08 (2H, m), 7.22 (2H, d, J=8.6 Hz), 7.52 (2H,d, J=8.6 Hz), 9.79 (1H, br s), 10.12 (1H, br s).

MS(FAB) m/z: 331 (M+H)⁺.

EXAMPLE 34 3-[4-(4-Chlorophenyl)-1-methylaminobutyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-26)

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-oxopropyl]-N-methylcarbamateobtained from Example 22a and (4-chlorobenzyl)triphenylphosphoniumchloride were treated using similar procedures to those described inExample from 22b to 22d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40-1.48 (1H, m), 1.58-1.66 (1H, m),2.20-2.28 (1H, m), 2.42 (3H, s), 2.40-2.57 (3H, m), 3.01 (3H, s), 3.11(3H, s), 3.94 (1H, br s), 6.99-7.28 (6H, m), 7.44-7.52 (2H, m), 9.77(1H, br s), 10.15 (1H, br s).

EXAMPLE 35 4-[4-(4-Chlorophenyl)-1-methylaminobutyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-26)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b, 3-methoxyphenol and(4-chlorobenzyl)triphenylphosphonium chloride were treated using similarprocedures to those described in Example 22 to afford the title compoundas an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.38-1.58 (2H, m), 2.20-2.26 (1H, m),2.39 (3H, s), 2.38-2.62 (3H, m), 3.01 (3H, s), 3.10 (3H, s), 3.90 (1H,br s), 6.99 (1H, d, J=8.4 Hz), 7.06 (1H, d, J=6.9 Hz), 7.11-7.24 (4H,m), 7.52 (1H, d, J=8.4 Hz), 9.77 (1H, br s), 10.15 (1H, br s).

EXAMPLE 36 4-[3-(3-Methoxyphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-87)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-methoxyphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.52-2.58 (1H, m),2.92-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.55-3.60 (1H, m), 3.75(3H, s), 3.91-3.96 (1H, m), 4.32-4.36 (1H, m), 6.36-6.38 (2H, m), 6.47(1H, dd, J=8.9 Hz, 1.9 Hz), 7.11 (1H, t, J=8.9 Hz), 7.18 (2H, d, J=8.6Hz), 7.60 (2H, d, J=8.6 Hz).

MS (FAB) m/z: 359 (M+H)⁺.

EXAMPLE 37 4-[3-(2-Methoxyphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-88)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-methoxyphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.56 (3H, s), 2.56-2.62 (1H, m),2.85-2.89 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.86-3.93 (1H, m), 3.90(3H, s), 4.08-4.11 (1H, m), 4.43-4.46 (1H, m), 6.81 (1H, d, J=7.9 Hz),6.86-6.91 (2H, m), -6.95-6.98 (1H, m), 7.18 (2H, d, J=8.6 Hz), 7.59 (2H,d, J=8.6 Hz).

MS (FAB) m/z: 359 (M+H)⁺.

EXAMPLE 38 4-[3-(3-chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-79)(a) t-Butyl[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamate

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-chlorophenol were treated using asimilar procedure to that described in Example 7f to afford the desiredcompound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41(9H, s), 2.30-2.41(2H, m), 2.60(3H,s), 3.02(3H, s), 3.10(3H, s), 4.00(2H, brs), 5.54(1H, brs), 6.77(1H, dd,J=8.2, 2.4 Hz), 6.86-6.93(2H, m), 7.10(2H, d, J=8.6 Hz), 7.18(1H, t,J=8.2 Hz), 7.28-7.30(2H, m).

(b) 4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride

t-Butyl[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 38a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.52-2.61 (1H, m),2.93-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.55-3.60 (1H, m),3.92-3.97 (1H, m), 4.31-4.35 (1H, m), 6.68 (1H, dd, J=8.1 Hz, 2.1 Hz),6.78 (1H, t, J=2.1 Hz), 6.90 (1H, dd, J=8.1 Hz, 2.1 Hz), 7.14 (1H, t,J=8.1 Hz), 7.19 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz).

MS (EI) m/z: 363 (M+H)⁺.

EXAMPLE 39 4-[3-(2-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-80)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-chlorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.55 (3H, s), 2.58-2.65 (1H, m),2.98-3.06 (1H, m), 3.00 (3H, s), 3.08 (3H, s), 3.59-3.65 (1H, m),4.11-4.16 (1H, m), 4.44-4.48 (1H, m), 6.75 (1H, dd, J=8.1 Hz, 1.3 Hz),6.87 (1H, td, J=8.1 Hz, 1.3 Hz), 7.13 (1H, td, J=8.1 Hz, 1.6 Hz), 7.17(2H, d, J=8.6 Hz), 7.33 (1H, dd, J=8.1 Hz, 1.6 Hz), 7.66 (2H, d, J=8.6Hz), 9.90 (1H, br s), 10.20 (1H, br s).

MS (EI) m/z: 363 (M+H)⁺.

EXAMPLE 40 4-(1-Methylamino-3-p-toluyloxypropyl)phenyl dimethylcarbamatehydrochloride (Exemplification Compound Number 1-82)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-methylphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.24 (3H, s), 2.46-2.54 (1H, m), 2.51(3H, s), 2.95-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.52-3.58 (1H,m), 3.90-3.94 (1H, m), 4.33-4.37 (1H, m), 6.68 (2H, d, J=8.5 Hz), 7.01(2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.5 Hz), 7.61 (2H, d, J=8.6 Hz).

MS (EI) m/z: 342 (M)⁺.

EXAMPLE 41 4-[3-(4-Chlorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-135)

4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 16d was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.60 (3H, s), 2.64-2.68 (1H, m), 2.90(3H, s), 2.90-2.98 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.50-3.54 (1H,m), 3.95-3.98 (1H, m), 4.26-4.28 (1H, m), 6.67 (2H, d, J=8.9 Hz), 7.18(2H, d, J=8.9 Hz), 7.23 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.6 Hz).

MS (EI) m/z: 376 (M)⁺.

EXAMPLE 42 4-[3-(4-Chlorophenyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-13)

4-Acetylphenol and 4-chlorobenzaldehyde were treated using similarprocedures to those described in Example 1 to afford the title compoundas an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.37 (3H, s), 2.31-2.53 (3H, m),2.68-2.79 (1H, m), 3.03 (3H, s), 3.12 (3H, s), 3.84 (1H, br s), 7.03(2H, d, J=8.2 Hz), 7.20 (2H, d, J=8.2 Hz), 7.22 (2H, d, J=8.1 Hz), 7.52(2H, d, J=8.1 Hz), 9.85 (1H, br s), 10.15 (1H, br s).

MS(EI) m/z: 347 (M+H)⁺.

EXAMPLE 43 4-[3-(2,4-Difluorophenoxy)-1-methylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-101)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2,4-difluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.50-2.61 (1H, m),2.92-3.05 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.58-3.67 (1H, m),4.02-4.08 (1H, m), 4.33-4.40 (1H, m), 6.67-6.85 (3H, m), 7.19 (2H, d,J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz).

MS(FAB) m/z: 365 (M+H)⁺.

EXAMPLE 44 4-[3-(2-Chloro-4-fluorophenoxy)-1-methylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-106)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-chloro-4-fluorophenol were treated usingsimilar procedures to those described in Example 7f and 79 to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54 (3H, s), 2.55-2.65 (1H, m),2.95-3.07 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.55-3.65 (1H, m),4.05-4.12 (1H, m), 4.38-4.45 (1H, m), 6.71 (1H, dd, J=9.1 Hz, 4.8 Hz),6.83-6.89 (1H, m), 7.10 (1H, dd, J=8.0 Hz, 3.0 Hz), 7.18 (2H, d, J=8.6Hz), 7.64 (2H, d, J=8.6 Hz).

MS(FAB) m/z: 381 (M+H)⁺.

EXAMPLE 45 4-[3-(4-Acetylphenoxy)-1-methylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-89)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-acetylphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (6H, s), 2.52-2.66 (1H, m),2.97-3.07 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.63-3.73 (1H, m),4.00-4.08 (1H, m), 4.30-4.38 (1H, m), 6.82 (2H, d, J=8.9 Hz), 7.19 (2H,d, J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz), 7.87 (2H, d, J=8.9 Hz).

MS(FAB) m/z: 371 (M+H)⁺.

EXAMPLE 46 4-[3-(2,4-Dichlorophenoxy)-1-methylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-107)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2,4-dichlorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.55-2.66 (1H, m),2.95-3.07 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.55-3.65 (1H, m),4.07-4.13 (1H, m), 4.36-4.45 (1H, m), 6.67 (1H, d, J=8.8 Hz), 7.10 (1H,dd, J=8.8 Hz, 2.5 Hz), 7.18 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=2.5 Hz),7.64 (2H, d, J=8.6 Hz), 10.05 (2H, br s).

MS(FAB) m/z: 397 (M+H)⁺.

EXAMPLE 47 4-[3-(3,4-Dichlorophenoxy)-1-methylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-110)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3,4-dichlorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, s), 2.57 (1H, br s), 2.98 (1H,br s), 3.01 (3H, s), 3.10 (3H, s), 3.52-3.62 (1H, m), 3.90-3.98 (1H, m),4.31 (1H, br s), 6.66 (1H, dd, J=8.8 Hz, 2.8 Hz), 6.88 (1H, d, J=2.8Hz), 7.20 (2H, d, J=8.1 Hz), 7.27 (1H, d, J=8.8 Hz), 7.59 (2H, d, J=8.1Hz), 9.93 (1H, br s), 10.30 (1H, br s).

MS(FAB) m/z: 397 (M+H)⁺.

EXAMPLE 48 4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-92)(a) t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]-N-methylcarbamate

Triphenylphosphine (420 mg, 1.6 mmol) was dissolved in tetrahydrofuran(4 ml) under an atmosphere of nitrogen and 40% solution of diethylazodicarboxylate in toluene (0.72 ml, 1.6 mmol) was added to thesolution. After stirring the resulting mixture for 30 minutes at roomtemperature, 4-nitrophenol (190 mg, 1.4 mmol) was added to the reactionmixture. After stirring this mixture for 30 minutes, t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b (400 mg, 1.1 mmol) was added and the resultingmixture was stirred for 5 hours. The reaction mixture was partitionedbetween water and ether. The organic layer was washed with water andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by chromatography on a silica gel column using hexane:ethylacetate=50:50 as the eluent to afford the desired compound (392 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.39(9H, s), 2.39-2.49(2H, m), 2.60(3H,s), 3.02(3H, s), 3.11(3H, s), 4.11-4.13(2H, m), 5.60(1H, br s), 6.95(2H,d, J=9.1 Hz), 7.11(2H, d, J=8.6 Hz), 7.27-7.31(2H, m), 8.20(2H, d, J=9.1Hz).

(b) 4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]-N-methylcarbamateobtained from Example 48a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.62-2.66 (1H, m), 3.01(3H, s), 3.01-3.10 (1H, m), 3.10 (3H, s), 3.72-3.75 (1H, m), 4.07-4.11(1H, m), 4.29-4.32 (1H, m), 6.86 (2H, d, J=9.2 Hz), 7.20 (2H, d, J=8.4Hz), 7.59 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=9.2 Hz).

IR(KBr) v_(max)cm⁻¹: 3430, 2941 2756, 2698, 2446, 1724.

MS m/z: 374 (M+H)⁺.

EXAMPLE 49 4-[3-(4-Aminophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate dihydrochloride (Exemplification Compound Number 1-95)(a) t-ButylN-[3-(4-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl)propyl]-N-methylcarbamate

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]-N-methylcarbamate(1.13 g, 2.4 mmol) obtained from Example 48a was dissolved in methanol(11 ml) and 5% palladium on charcoal (110 mg) was added to the solution.The resulting mixture was stirred at room temperature under anatmosphere of hydrogen for 1 hour. The catalyst was filtered off and thesolvent of the filtrate was evaporated under reduced pressure. Theresidue was recrystallized from a mixture of ethyl acetate and hexane toafford the desired compound (820 mg) as crystals (mp 146-149° C.).

(b) 4-[3-(4-Aminophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatedihydrochloride

t-ButylN-[3-(4-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 49a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 2.27-2.36 (1H, m), 2.38 (3H, s),2.60-2.62 (1H, m), 2.90 (3H, s), 3.03 (3H, s), 3.61-3.63 (1H, m),3.94-3.96 (1H, m), 4.38-4.41 (1H, m), 6.92 (2H, d, J=8.8 Hz), 7.19-7.25(4H, m), 7.55 (2H, d, J=8.6 Hz).

MS (FAB) m/z: 344 (M+H)⁺.

EXAMPLE 50 4-[3-(4-Acetylaminophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-97)(a) t-Butyl[3-(4-acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methylcarbamate

t-ButylN-[3-(4-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamate(100 mg, 0.23 mmol) obtained from Example 49a was dissolved in pyridine(1 ml) under an atmosphere of nitrogen, and acetic anhydride (0.026 ml,0.28 mmol) was added to the solution. The resulting mixture was stirredat room temperature for 30 minutes. To the reaction mixture was added0.5N aqueous hydrochloric acid solution and the mixture was extractedwith ethyl acetate. The organic layer was washed with 0.5N aqueoushydrochloric acid solution, water and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column using ethyl acetate as the eluent to afford the desiredcompound (106 mg).

¹H-NMR (400 MHz, CDCl₃) δ: 1.43(9H, s), 2.32-2.43(2H, m), 2.61(3H, s),3.01(3H, s), 3.10(3H, s), 3.97(2H, brs), 5.52(1H, brs), 6.22(1H, s),6.27-6.31(2H, m), 7.03(1H, t, J=8.0 Hz), 7.09(2H, d, J=8.5 Hz), 7.29(2H,brs).

(b) 4-[3-(4-Acetylaminophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride

t-Butyl[3-(4-Acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methylcarbamateobtained from Example 50a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.13 (3H, s), 2.43-2.53 (1H, m), 2.47(3H, s), 2.88-2.90 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.57-3.62 (1H,m), 3.87-3.89 (1H, m), 4.32-4.34 (1H, m), 6.71 (2H, d, J=8.7 Hz), 7.18(2H, d, J=8.1 Hz), 7.26-7.35 (2H, m), 7.59 (2H, d, J=8.1 Hz), 7.63 (1H,s).

MS (FAB) m/z: 386 (M+H)⁺.

EXAMPLE 51 4-[3-(3-Chlorophenoxy)-1-dimethylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-136)

4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 38b was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.60 (3H, brs), 2.60-2.71 (1H, m),2.88-2.97 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.49-3.55 (1H, m),3.96-4.00 (1H, m), 4.24-4.29 (1H, m), 6.64 (1H, ddd, J=8.4 Hz, 2.2 Hz,0.8 Hz), 6.74 (1H, t, J=2.2 Hz), 6.92 (1H, ddd, J=8.4 Hz, 2.2 Hz, 0.8Hz), 7.15 (1H, t, J=8.2 Hz), 7.23 (2H, d, J=8.7 Hz), 7.57 (2H, d, J=8.7Hz).

MS (FAB) m/z: 377 (M+H)⁺.

EXAMPLE 52 4-[3-(2-Chlorophenoxy-1-dimethylaminopropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-137)

4-[3-(2-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 39 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.58 (3H, s), 2.69-2.77 (1H, m),2.90-3.00 (4H, m), 3.01 (3H, s), 3.09 (3H, s), 3.47-3.53 (1H, m),4.13-4.17 (1H, m), 4.32-4.35 (1H, m), 6.73 (1H, dd, J=7.9 Hz, 1.3 Hz),6.89 (1H, td, J=7.9 Hz, 1.3 Hz), 7.15 (1H, td, J=7.9 Hz, 1.6 Hz), 7.20(2H, d, J=8.7 Hz), 7.34 (1H, dd, J=7.9 Hz, 1.6 Hz), 7.66 (2H, d, J=8.7Hz).

MS (FAB) m/z: 377 (M+H)⁺.

EXAMPLE 53 4-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-94)(a) t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(3-nitrophenoxy)propyl]-N-methylcarbamate

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-nitrophenol were treated using a similarprocedure to that described in Example 7f to afford the desired comound.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40(9H, s), 2.39-2.48(2H, m), 2.61(3H, s),3.02(3H, s), 3.11(3H, s), 4.09-4.15(2H, m), 5.63(1H, brs), 7.11(2H, d,J=8.6 Hz), 7.23(1H, d, J=8.2 Hz), 7.31(2H, d, J=8.6 Hz), 7.43(1H, t,J=8.2 Hz), 7.72(1H, s), 7.83(1H, d, J=8.2 Hz).

(b) 4-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(3-nitrophenoxy)propyl]-N-methylcarbamateobtained from Example 53a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.64-2.67 (1H, m),2.96-3.09 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.70-3.74 (1H, m),4.06-4.10 (1H, m), 4.32-4.36 (1H, m), 7.15 (1H, dd, J=8.2 Hz, 2.4 Hz),7.21 (1H, d, J=8.4 Hz), 7.39 (1H, t, J=8.2Hz), 7.59 (1H, s), 7.60 (2H,d, J=8.4 Hz), 7.80 (1H, dd, J=8.2 Hz, 2.4 Hz).

MS (FAB) m/z: 374 (M+H)⁺.

EXAMPLE 54 4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-102)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3,4-difluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, br s), 2.55-2.62 (1H, m),2.92-3.02 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.52-3.59 (1H, m),3.89-3.95 (1H, m), 4.28-4.35 (1H, m), 6.45-6.51 (1H, m), 6.61 (1H, ddd,J=11.9 Hz, 6.6 Hz, 2.2 Hz), 7.00 (1H, q, J=9.4 Hz), 7.19 (2H, d, J=8.5Hz), 7.59 (2H, d, J=8.5 Hz) 9.93 (1H, br s), 10.30 (1H, br s).

MS(FAB) m/z: 365 (M+H)⁺.

EXAMPLE 55 4-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-104)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl)-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-chloro-3-fluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, br s), 2.51-2.62 (1H, m),2.91-3.04 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.53-3.62 (1H, m),3.90-3.98 (1H, m), 4.27-4.34 (1H, m), 6.52-6.55 (1H, m), 6.60 (1H, dd,J=10.7 Hz, 2.7 Hz), 7.18-7.25 (3H, m), 7.59 (2H, d, J=8.3 Hz), 9.94 (1H,br s), 10.32 (1H, br s).

MS(FAB) m/z: 381 (M+H)⁺.

EXAMPLE 56 4-[3-(4-Cyanophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-91)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-hydroxybenzonitrile were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, br s), 2.55-2.68 (1H, m),2.95-3.05 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.64-3.72 (1H, m),3.98-4.07 (1H, m), 4.25-4.35 (1H, m), 6.84 (2H, d, J=8.8 Hz), 7.19 (2H,d, J=8.3 Hz), 7.53 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.3 Hz), 9.96 (1H,br s), 10.36 (1H, br s).

MS(EI) m/z: 354 (M+H)⁺.

EXAMPLE 57 4-[3-(4-Bromophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-81)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-bromophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, br s), 2.52-2.62 (1H, m),2.92-3.03 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.53-3.61 (1H, m),3.88-3.97 (1H, m), 4.28-4.38 (1H, m), 6.66 (2H, d, J=9.0 Hz), 7.18 (2H,d, J=8.5 Hz), 7.31 (2H, d, J=9.0 Hz), 7.59 (2H, d, J=8.5 Hz), 9.91 (1H,br s), 10.22 (1H, br s).

MS(FAB) m/z: 407 (M+H)⁺.

EXAMPLE 58 4-[3-(4-Fluoro-2-methylphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-111)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-fluoro-2-methylphenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.19 (3H, s), 2.51 (3H, br s), 2.53-2.63(1H, m), 2.93-3.03 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.54-3.62 (1H,m), 3.89-3.97 (1H, m), 4.28-4.37 (1H, m), 6.53 (1H, dd, J=8.7 Hz, 4.5Hz), 6.73 (1H, td, J=8.7 Hz, 3.0 Hz), 6.82 (1H, dd, J=8.7 Hz, 3.0 Hz),7.19 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz) 9.94 (1H, br s), 10.32(1H, br s)

MS(FAB) m/z: 361 (M+H)⁺.

EXAMPLE 59 4-[1-Methylamino-3-m-toluyloxypropyl]phenyl dimethylcarbamatehydrochloride (Exemplification Compound Number 1-83)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-methylphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.28 (3H, s) 2.52 (3H, s), 2.48-2.60 (1H,m), 2.90-3.03 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.53-3.61 (1H, m),3.89-3.97 (1H, m), 4.32-4.40 (1H, m), 6.56-6.62 (2H, m), 6.73 (1H, d,J=7.6 Hz), 7.10 (1H, t, J=7.6 Hz), 7.18 (2H, d, J=8.5 Hz), 7.61 (2H, d,J=8.5 Hz), 9.93 (1H, br s), 10.25 (1H, br s).

MS(EI) m/z: 343 (M+H)⁺.

EXAMPLE 60 4-[3-(3,4-Dimethylphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-114)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3,4-dimethylphenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.15 (3H, s), 2.18 (3H, s), 2.51 (3H, brs), 2.45-2.58 (1H, m), 2.87-3.00 (1H, m), 3.00 (3H, s), 3.08 (3H, s),3.48-3.57 (1H, m), 3.86-3.94 (1H, m), 4.34 (1H, br s), 6.51 (1H, dd,J=8.2 Hz, 2.6 Hz), 6.59 (1H, d, J=2.6 Hz), 6.95 (1H, d, J=8.2 Hz), 7.17(2H, d, J=8.6 Hz), 7.60 (2H, d, J=8.6 Hz), 9.90 (1H, br s), 10.24(1H, brs).

MS(FAB) m/z: 357 (M+H)⁺.

EXAMPLE 61 (R)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-79)(a) Methyl (R)-3-t-butoxycarbonylamino-3-(4-hydroxyphenyl)propionate

Methyl (R)-3-amino-3-(4-hydroxyphenyl)propionate, which was synthesizedaccording to the method described in Tetrahedron: Asymmetry, 2, 183,(1991), was treated using a similar procedure to that described inExample 6a to give the desired compound. The product was recrystallizedfrom a mixture of ethyl acetate and hexane to afford the desiredcompound (mp 130-132° C.), which had greater than 99% optical purity.The optical purity was determined by HPLC on a Chiralcel OD column(product of Daisel Chemical Industry Co. Ltd.) using hexane:isopropylalcohol=95:5 as the eluent.

(b) t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate

Methyl (R)-3-t-butoxycarbonylamino-3-(4-hydroxyphenyl)propionateobtained from Example 61a was treated using similar procedures to thosedescribed in Example 7d and 7e to afford the desired product.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 1.92-1.97 (1H, m),2.14-2.20 (1H, m), 2.43 (1H, br), 3.01 (3H, s), 3.10 (3H, s), 3.51-3.58(2H, m), 3.73-3.77 (1H, br), 5.57-5.59 (1H, m), 7.10 (2H, d, J=7.7 Hz),7.28 (2H, d, J=7.7 Hz).

(c) t-Butyl(R)-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]carbamate

t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 61b and 3-chlorophenol were treated using asimilar procedure to that described in Example 7f to afford the desiredcompound.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.41 (9H, s), 2.34-2.44 (2H, m), 3.02(3H, s), 3.11 (3H, s), 4.00 (2H, br s), 5.54 (2H, br s), 6.78 (1H, d,J=8.1 Hz), 6.89 (1H, s), 6.94 (1H, d, J=8.1 Hz), 7.12 (2H, d, J=8.4 Hz),7.17 (1H, t, J=8.1 Hz), 7.29 (2H, br s).

(d) t-Butyl(R)—N-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamate

N,N-dimethylformamide (30 ml) was added to sodium hydride (1.75 g, 40mmol) under an atmosphere of nitrogen, and to the sodium hydride wasadded a solution of t-butyl(R)-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]carbamate(7.00 g, 16 mmol) obtained from Example 61c in N,N-dimethylformamide inan ice bath. The mixture was stirred for 30 minutes and then methyliodide (1.9 ml, 30 mmol) was added thereto. The resulting mixture waswarmed to room temperature and then stirred overnight. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with water and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column using hexane:ethyl acetate=95:5 to 85:15 to afford thedesired compound (6.14 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41 (9H, s), 2.35-2.44 (3H, s), 2.60(3H, s) 3.02 (3H, s), 3.10 (3H, s), 4.00 (2H, br), 5.54 (1H, br), 6.78(1H, d, J=8.3 Hz), 7.10 (2H, d, J=8.4 Hz), 7.18 (1H, t, J=8.3 Hz), 7.29(2H, m).

(e) (R)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride

t-Butyl(R)—N-[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 61d was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.52-2.61 (1H, m),2.93-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.55-3.60 (1H, m),3.92-3.97 (1H, m), 4.31-4.35 (1H, m), 6.68 (1H, dd, J=8.1 Hz, 2.1 Hz),6.78 (1H, t, J=2.1 Hz), 6.90 (1H, dd, J=8.1 Hz, 2.1 Hz), 7.14 (1H, t,J=8.1 Hz), 7.19 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz).

MS(EI) m/z: 363 (M+H)⁺

EXAMPLE 62 (R)-4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-78)

t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 61b and 4-chlorophenol were treated using similarprocedures to those described in Example from 61c to 61e to afford thetitle compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, s), 2.51-2.59 (1H, m),2.94-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.55-3.59 (1H, m),3.91-4.13 (1H, m), 4.30-4.34 (1H, m), 6.71 (2H, d, J=9.0 Hz), 7.15-7.19(4H, m), 7.59 (2H, d, J=8.6 Hz).

[α]_(D) ²²+72 (c 0.37, CHCl₃)

EXAMPLE 63 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyldiethylcarbamate hydrochloride (Exemplification Compound Number 1-7) (a)t-ButylN-[3-(4-chlorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate

t-Butyl[3-(4-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 16c was treated using a similar procedure to thatdescribed in Example 6b to afford the desired compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41 (9H, s), 2.29-2.39 (2H, m), 2.57(3H, s), 3.97 (2H. br s), 5.21 (1H. br s), 5.51 (1H, br s), 6.79-6.82(4H, m), 7.17 (2H, d, J=7.4 Hz), 7.22 (2H, d, J=8.9 Hz).

(b) 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl diethylcarbamatehydrochloride

t-ButylN-[3-(4-chlorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamateobtained from Example 63a was treated using similar procedures to thosedescribed in Example 23 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.18-1.27 (6H, m), 2.50 (3H, s),2.49-2.58 (1H, m), 2.94-3.01 (1H, m), 3.34-3.45 (4H, m), 3.54-3.59 (1H,m), 3.90-3.96 (1H, m), 4.32 (1H, br s), 6.71 (2H, d, J=9.2 Hz), 7.17(2H, d, J=8.9 Hz), 7.19 (2H, d, J=9.2 Hz), 7.59 (2H, d, J=8.9 Hz), 9.95(1H, br s), 10.31 (1H, br s).

MS(EI) m/z: 391

(M+H)⁺

EXAMPLE 64 4-[3-(3-Aminophenoxy)1-methylaminopropyl]phenyldimethylcarbamate dihydrochloride (Exemplification Compound Number 1-96)(a) t-ButylN-[3-(3-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamate

t-ButylN-[1-[4-dimethylcarbamoyloxy]phenyl-3-(3-nitrophenoxy)propyl]-N-methylcarbamateobtained from Example 53a was treated in a similar procedure to thatdescribed in Example 49a to afford the desired compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.41 (9H, s), 2.16 (3H, s), 2.28-2.33(1H,m), 2.34-2.47(1H, m), 2.60(3H, s), 3.02(3H, s), 3.11(3H, s),3.98-4.06(2H, m), 5.52(1H, brs), 6.62(1H, d, J=6.7 Hz), 6.99(1H, brs),7.08-7.12(3H, m), 7.19(1H, t, J=8.2 Hz), 7.27-7.33(2H, m)

(b) 4-[3-(3-Aminophenoxy)1-methylaminopropyl]phenyl dimethylcarbamatedihydrochloride

t-ButylN-[3-(3-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 64a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound-as an amorphoussolid.

¹H-NMR (400 MHz, DMSO-d6) δ ppm: 2.28-2.39 (1H, m), 2.39 (3H, t, J=5.0Hz), 2.59-2.64 (1H, m), 2.90 (3H, s), 3.03 (3H, s), 3.56-3.63 (1H, m),3.90-3.95 (1H, m), 4.38-4.42 (1H, m), 6.66-6.75 (3H, m), 7.19-7.27 (3H,m), 7.56 (2H, d, J=8.4 Hz).

MS (FAB) m/z: 344 (M+H)⁺.

EXAMPLE 65 4-[3-(3-Acetylaminophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-98)(a) t-Butyl[3-(3-acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methylcarbamate

t-ButylN-[3-(3-aminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 64a was treated using a similar procedure to thatdescribed in Example 50a to afford the desired compound.

(b) 4-[3-(3-Acetylaminophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride

t-Butyl[3-(3-acetylaminophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]methylcarbamateobtained from Example 65a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.13 (3H, s), 2.48 (4H, br s), 2.86 (1H,br s), 3.03 (3H, s), 3.12 (3H, s), 3.74 (1H, br s), 3.86 (1H, br s),4.28 (1H, br s), 6.50 (1H, d, J=5.9 Hz), 6.59 (1H, br s), 7.13-7.16 (3H,m), 7.36-7.37 (1H, m), 7.57 (2H, br s), 8.41 (1H, br s), 9.82 (1H, brs), 10.01 (1H, br s).

MS (FAB) m/z: 386 (M+H)⁺.

EXAMPLE 66 4-[1-Methylamino-3-(2-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-93)

t-ButylN-(1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-nitrophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.56 (3H, s), 2.62-2.70 (1H, m),2.95-3.03 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.75-3.81 (1H, m),4.28-4.33 (1H, m), 4.46-4.50 (1H, m), 6.96 (1H, dd, J=8.0 Hz, 1.0 Hz),7.02 (1H, td, J=8.0 Hz, 1.0 Hz), 7.17 (2H, d, J=8.6 Hz), 7.48 (1H, td,J=8.0 Hz, 1.6 Hz), 7.69 (2H, d, J=8.6 Hz), 7.87 (1H, dd, J=8.0 Hz, 1.6Hz).

MS (EI) m/z: 374 (M+H)⁺.

EXAMPLE 67 4-[1-Methylamino-3-phenoxypropyl]phenyl dimethylcarbamatehydrochloride (Exemplification Compound Number 1-74)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and phenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.48-2.59 (1H, m), 2.52 (3H, s),2.93-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.56-3.62 (1H, m),3.94-3.98 (1H, m), 4.34-4.38 (1H, m), 6.79 (2H, d, J=8.5 Hz), 6.91 (1H,t, J=7.3 Hz), 7.17-7.24 (4H, m), 7.61 (2H, d, J=8.5 Hz).

MS (EI) m/z: 329 (M+H)⁺.

EXAMPLE 68 4-[3-(3-Fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-76)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-fluorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.52-2.61 (1H, m),2.93-3.00 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.55-3.61 (1H, m),3.93-3.97 (1H, m), 4.32-4.35 (1H, m), 6.50 (1H, dt, J=10.8 Hz, 2.3 Hz),6.57 (1H, dd, J=7.3 Hz, 2.3 Hz), 6.62 (1H, td, J=8.3 Hz, 2.3 Hz),7.13-7.20 (3H, m), 7.60 (2H, d, J=8.6 Hz) 9.93 (1H, br s), 10.28 (1H, brs).

MS (FAB) m/z: 347 (M+H)⁺.

EXAMPLE 69 4-[3-(2-Fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-77)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-fluorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.53-2.63 (1H, m),2.97-3.09 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.61-3.67 (1H, m),4.06-4.13 (1H, m), 4.39-4.41 (1H, m), 6.79-6.90 (2H, m), 6.96-7.06 (2H,m), 7.18 (2H, d, J=8.5 Hz), 7.65 (2H, d, J=8.5 Hz), 9.91 (1H, br s),10.23 (1H, br s).

MS (EI) m/z: 347 (M+H)⁺.

EXAMPLE 70 4-[1-Dimethylamino-3-(3-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-133)

4-[3-(3-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 68 was treated using a similar procedure to thatdescribed in Example 3 to afford the titile compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.60 (3H, s), 2.60-2.73 (1H, m), 2.91(3H, s), 2.91-3.02 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.49-3.55 (1H,m), 3.96-4.00 (1H, m), 4.26-4.29 (1H, m), 6.46 (1H, dt, J=10.7 Hz, 2.3Hz), 6.53 (1H, dd, J=8.3 Hz, 2.3 Hz), 6.64 (1H, td, J=8.3 Hz, 2.3 Hz),7.14-7.24 (3H, m), 7.58 (2H, d, J=8.5 Hz).

MS (EI) m/z: 360 (M)⁺.

EXAMPLE 71 4-[1-Dimethylamino-3-(2-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-134)

4-[3-(2-Fluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 69 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.58 (3H, s), 2.68-2.73 (1H, m), 2.95(4H, br s), 3.01 (3H, s), 3.10 (3H, s), 3.49-3.56 (1H, m), 4.09-4.15(1H, m), 4.31 (1H, br s), 6.78 (1H, t, J=8.3 Hz), 6.87-6.92 (1H, m),6.97-7.08 (2H, m), 7.21 (2H, d, J=7.9 Hz), 7.64 (2H, d, J=7.9 Hz).

MS (EI) m/z: 360 (M)⁺.

EXAMPLE 72 4-[3-(3-Acetylphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-90)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-acetylphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.47-2.66 (1H, m), 2.53 (3H, s), 2.56(3H, s), 2.93-3.06 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.61-3.70 (1H,m), 3.98-4.07 (1H, m), 4.32-4.40 (1H, m), 7.02 (1H, dd, J=7.9 Hz, 2.5Hz), 7.18 (2H, d, J=8.5 Hz), 7.32 (1H, t, J=7.9 Hz), 7.34 (1H, br s),7.51 (1H, d, J=7.9 Hz), 7.60 (2H, d, J=8.5 Hz), 10.10 (2H, br s).

MS(EI) m/z: 371 (M+H)⁺.

EXAMPLE 73 4-[3-(4-chloro-3-methylphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-113)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-chloro-3-methylphenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.28 (3H, s), 2.50-2.62 (1H, m), 2.51(3H, br s), 2.89-3.05 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.50-3.59(1H, m), 3.86-3.95 (1H, m), 4.27-4.37 (1H, m), 6.55 (1H, dd, J=8.7 Hz,2.9 Hz), 6.65 (1H, d, J=2.9 Hz), 7.15 (1H, d, J=8.7 Hz), 7.18 (2H, d,J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 9.96 (1H, br s), 10.33 (1H, br s).

MS(EI) m/z: 377 (M+H)⁺.

EXAMPLE 74 4-[3-(3-Chloro-4-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-109)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-chloro-4-fluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, br s), 2.50-2.63 (1H, m),2.91-3.04 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.51-3.60 (1H, m),3.88-3.97 (1H, m), 4.25-4.36 (1H, m), 6.65 (1H, dt, J=8.9 Hz, 3.0 Hz),6.81 (1H, dd, J=6.0 Hz, 3.0 Hz), 6.99 (1H, t, J=8.9 Hz), 7.20 (2H, d,J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz), 9.98 (1H, br s), 10.34 (1H, br s).

MS(EI) m/z: 381 (M+H)⁺.

EXAMPLE 75 4-[3-(4-Acetylphenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-146)

4-[3-(4-Acetylphenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 45 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.62 (3H, br s), 2.67-2.79(1H, br s), 2.90 (3H, br s), 2.99 (1H, br s), 3.02 (3H, s), 3.10 (3H,s), 3.63 (1H, br s), 4.06 (1H, br s), 4.30 (1H, br s), 6.78 (2H, d,J=8.7 Hz), 7.22 (2H, d, J=8.2 Hz), 7.57 (2H, d, J=8.2 Hz), 7.87 (2H, d,J=8.7 Hz).

MS(EI) m/z: 384 (M+H)⁺.

EXAMPLE 76 4-[3-(3,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-159)

4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 54 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.61 (3H, br s), 2.60-2.75 (1H, m), 2.90(3H, br s), 2.88-3.00 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.45-3.55(1H, m), 3.88-3.98 (1H, m), 4.22-4.31 (1H, br s), 6.40-6.47 (1H, m),6.56 (1H, ddd, J=11.7 Hz, 6.5 Hz, 2.9 Hz,), 7.01 (1H, q, J=9.4 Hz), 7.23(2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz).

MS(EI) m/z: 378 (M+H)⁺.

EXAMPLE 77 4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyldiethylcarbamate hydrochloride (Exemplification Compound Number 1-8)

t-Butyl[3-(3-chlorophenoxy)-1-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 38a was treated using similar procedures to thosedescribed in Example 63 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.18-1.28 (6H, m), 2.51 (3H, s),2.50-2.61 (1H, m), 2.94-3.02 (1H, m), 3.36-3.44 (4H, m), 3.54-3.59 (1H,m), 3.91-3.96 (1H, m), 4.34 (1H, br s), 6.68 (1H, d, J=8.5 Hz), 6.77(1H, s), 6.89 (1H, d, J=8.5 Hz), 7.13 (1H, t, J=8.5 Hz), 7.20 (2H, d,J=8.2 Hz), 7.60 (2H, d, J=8.2 Hz), 9.95 (1H, br s), 10.28 (1H, br s).

EXAMPLE 78 4-[3-(4-Chloro-3-fluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-161)

4-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate obtained from Example 55 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.61 (3H, br s), 2.62-2.75 (1H, m), 2.90(3H, br s), 2.96 (1H, br s), 3.02 (3H, s), 3.11 (3H, s), 3.46-3.55 (1H,m), 3.91-4.01 (1H, m), 4.26 (1H, br s), 6.49 (1H, dd, J=8.8 Hz, 1.8 Hz),6.55 (1H, dd, J=10.6 Hz, 2.6 Hz,), 7.21 (2H, d, J=8.6 Hz), 7.23 (1H, d,J=8.8 Hz), 7.55 (2H, d, J=8.6 Hz).

MS(EI) m/z: 394(M+H)⁺.

EXAMPLE 79 4-[3-(3,5-Difluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-103)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3,5-difluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, br s), 2.52-2.63 (1H, m),2.91-3.03 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.52-3.61 (1H, m),3.90-3.98 (1H, m), 4.30 (1H, br s), 6.32 (2H, dd, J=8.8 Hz, 2.1 Hz),6.38 (1H, tt, J=9.0 Hz, 2.1 Hz), 7.20 (2H, d, J=8.5 Hz), 7.59 (2H, d,J=8.5 Hz), 9.99 (1H, br s), 10.38 (1H, br s).

MS(EI) m/z: 365 (M+H)⁺.

EXAMPLE 80 4-[1-Methylamino-3-(3,4,5-trifluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-117)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3,4,5-trifluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, br s), 2.52-2.63 (1H, m),2.92-3.03 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.49-3.58 (1H, m),3.87-3.95 (1H, m), 4.28 (1H, br s), 6.37-6.47 (2H, m), 7.20 (2H, d,J=8.6 Hz), 7.59 (2H, d, J=8.6 Hz), 9.99 (1H, br s), 10.34 (1H, br s).

MS(EI) m/z: 381 (M+H)⁺.

EXAMPLE 81 (S)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-79)(a) t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate

Methyl (S)-3-amino-3-(4-hydroxyphenyl)propionate, which was synthesizedaccording to the method described in Tetrahedron: Asymmetry, 2, 183,(1991), was treated using similar procedures to those described inExample 61a and 61b to afford the desired compound.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.42 (9H, s), 2.78-2.90 (2H, m), 3.00(3H, s), 3.09 (3H, s), 3.62 (3H, s), 5.09 (1H, br s), 5.42 (1H, br s),7.07 (2H, d, J=9.0 Hz), 7.28 (2H, d, J=9.0 Hz).

(b) (S)-4-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride

t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example B8a and 3-chlorophenol were treated using similarprocedures to those described Example 7f, 61d and 61e to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52,(3H, s), 2.52-2.61 (1H, m),2.93-3.05 (1H, m), 3.00 (3H, s), 3.09 (3H, s), 3.55-3.60 (1H, m),3.92-3.97 (1H, m), 4.31-4.35 (1H, m), 6.68 (1H, dd, J=8.1 Hz, 2.1 Hz),6.78 (1H, t, J=2.1 Hz), 6.90 (1H, dd, J=8.1 Hz, 2.1 Hz), 7.14 (1H, t,J=8.1 Hz), 7.19 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz).

EXAMPLE 82 (S)-4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-78)

t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 81a and 4-chlorophenol were treated using similarprocedures to those described Example 7f, 61d and 61e to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, s), 2.51-2.59 (1H, m),2.94-3.01 (1H, m), 3.01 (3H, s), 3.09 (3H, s), 3.55-3.59 (1H, m),3.91-4.13 (1H, m), 4.30-4.34 (1H, m), 6.71 (2H, d, J=9.0 Hz), 7.15-7.19(4H, m), 7.59 (2H, d, J=8.6 Hz).

EXAMPLE 83 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenylN-ethyl-N-methylcarbamate hydrochloride (Exemplification Compound Number1-10) (a) t-ButylN-[3-(4-chlorophenoxy)-1-[4-(N-ethyl-N-methylcarbamoyloxy)phenyl]propyl]-N-methylcarbamate

t-ButylN-[3-(4-chlorophenoxy)-1-(3-hydroxyphenyl)propyl]-N-methylcarbamate (200mg, 0.51 mmol) obtained from Example 63a was dissolved indichloromethane (3 ml) and to the solution was addedN,N-carbonyldiimidazole (165 mg, 1.0 mmol). The mixture was stirred atroom temperature overnight and then ethylamine (0.09 ml, 1.0 mmol) wasadded thereto. The resulting mixture was stirred for one day. Thereaction mixture was partitioned between water and dichloromethane. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column using hexane:ethyl acetate=80:20to 60:40 as the eluent to afford the desired compound (96 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.17-1.26 (6H, m), 1.41 (9H, s),2.33-2.57 (2H, m), 2.59 (3H, s), 2.99 (3H, s), 3.07 (3H, s), 3.41(2H, q,J=7.1 Hz), 3.46(2H, q, J=7.1 Hz), 3.98 (2H, br s), 5.56 (1H, br s), 6.81(2H, d, J=9.0 Hz), 7.10 (2H, d, J=6.4 Hz), 7.22 (2H, d, J=9.0 Hz), 7.29(2H, d, J=6.4 Hz).

(b) 4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenylN-ethyl-N-methylcarbamate hydrochloride

t-ButylN-[3-(4-chlorophenoxy)-1-[4-(N-ethyl-N-methylcarbamoyloxy)phenyl]propyl]-N-methylcarbamateobtained from Example 83a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.19 and 1.23 (3H, t, J=7.1 Hz), 2.50(3H, s), 2.49-2.60 (1H, m), 2.92-3.00 (1H, m), 2.98 and 3.06 (3H, s),3.40 and 3.46 (2H, q, J=7.1 Hz), 3.53-3.60 (1H, m), 3.89-3.96 (1H, m),4.32 (1H, br s), 6.71 (2H, d, J=8.9 Hz), 7.15-7.20 (4H, m), 7.59 (2H, d,J=8.4 Hz), 9.93 (1H, br s), 10.30 (1H, br s).

EXAMPLE 84 4-[3-(3,5-Difluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-160)

4-[3-(3,5-Difluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 79 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.60 (3H, br s), 2.63-2.75 (1H, m), 2.90(3H, br s), 2.92-3.03 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.44-3.55(1H, m), 3.92-4.00 (1H, m), 4.20-4.28 (1H, m), 6.23-6.32 (2H, m), 6.40(1H, tt, J=8.9 Hz, 2.2 Hz) 7.24 (2H, d, J=8.5 Hz), 7.56 (2H, d, J=8.5Hz)

MS(EI) m/z: 378 (M+H)⁺.

EXAMPLE 85 4-[3-(2,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-158)

4-[3-(2,4-Difluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained from Example 43 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.59 (3H, br s), 2.63-2.75 (1H, m), 2.94(3H, br s), 2.90-3.01 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.47-3.57(1H, m), 4.02-4.08 (1H, m), 4.25-4.34 (1H, m), 6.68-6.78 (2H, m),6.79-6.87 (1H, m), 7.23 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz).

MS(EI) m/z: 378 (M+H)⁺.

EXAMPLE 86 4-[1-Dimethylamino-3-(3-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-151)

4-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamateobtained from Example 53 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.62 (3H, d, J=4.7 Hz), 2.70-2.78 (1H,m), 2.89 (3H, d, J=4.7 Hz), 2.99-3.09 (1H, m), 3.02 (3H, s), 3.11 (3H,s), 3.63-3.69 (1H, m), 4.06-4.09 (1H, m), 4.29-4.34 (1H, m), 7.10 (1H,dd, J=8.2 Hz, 2.3 Hz), 7.24 (2H, d, J=8.7 Hz), 7.40 (1H, t, J=8.2 Hz),7.55-7.57 (3H, m), 7.81 (1H, dd, J=8.2 Hz, 2.3 Hz).

MS (EI) m/z: 387 (M)⁺.

EXAMPLE 87 4-(3-(3-Chlorophenylamino)-1-methylaminopropyl]phenyldimethylcrbamate dihydrochloride (Exemplification Compound Number 1-52)(a) t-ButylN-[3-[N-t-butoxycarbony-N-methylamino]-3-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-(3-chlorophenyl)carbamate

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl-3-hydroxypropyl]-N-methylcarbamate(100 mg, 0.28 mmol) obtained from Example 16b was dissolved intetrahydrofuran (1.5 ml) under an atmosphere of nitrogen. To thesolution were added sequentially triethylamine (0.07 ml, 0.50 mmol) andmethanesulfonyl chloride (0.03 ml, 0.34 mmol) in an ice bath. Theresulting mixture was stirred at room temperature for 45 minutes. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the methanesulfonate. On the other handN,N-dimethylformamide (1.5 ml) was added to sodium hydride (15 mg, 0.33mmol) and to the sodium hydride was added a solution of t-butyl(3-chlorophenyl)carbamate (75 mg, 0.33 mmol) in N,N-dimethylformamide inan ice bath. This mixture was stirred for 30 minutes and then a solutionof the methanesulfonate obtained above in N,N-dimethylformamide wasadded thereto. The resulting mixture was stirred at room temperature 2days. The reaction mixture was partitioned between water and ether. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column using hexane:ethyl acetate 60:40 as the eluent to afford thedesired compound (106 mg)

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.44(9H, s), 1.47(9H, s), 2.10-2.18(2H,m), 2.56(3H, s), 3.01(3H, s) 3.09(3H, s), 3.67(2H, brs), 5.44(1H, brs),7.06(2H, d, J=8.6 Hz), 7.11(1H, d, J=8.3 Hz), 7.17-7.29(5H, m).

(b) 4-[3-(3-Chlorophenylamino)-1-methylaminopropyl]phenyldimethylcarbamate dihydrochloride

t-ButylN-[3-[N-t-butoxycarbony-N-methylamino]-3-[(4-dimethylcarbamoyloxy)phenyl]propyl]-N-(3-chlorophenyl)carbamateobtained from Example 87a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.46 (3H, s), 2.77-2.82 (1H, m), 3.01(3H, s), 3.10 (3H, s), 3.21 (1H, t, J=10.7 Hz), 3.36 (2H, br s), 4.08(1H, br s), 7.25 (2H, d, J=8.0 Hz), 7.33 (2H, d, J=6.7 Hz), 7.46 (1H, brs), 7.56 (1H, s), 7.63 (2H, br s).

MS (EI) m/z: 361 (M)⁺.

EXAMPLE 88 4-[3-(3-Fluoro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-195)

3-Fluoro-4-nitrophenol was treated using similar procedures to thosedescribed in Example 48 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.62-2.68 (1H, m), 3.01(3H, s), 3.01-3.07 (1H, m), 3.10 (3H, s), 3.72-3.76 (1H, m), 4.08-4.10(1H, m), 4.23-4.31 (1H, m), 6.63-6.68 (2H, m), 7.21 (2H, d, J=8.6 Hz),7.59 (2H, d, J=8.6 Hz), 8.05 (1H, t, J=8.9 Hz).

MS (FAB) m/z: 392 (M+H)⁺.

EXAMPLE 89 4-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-149)

4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamateobtained from Example 48b was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.62 (3H, br s), 2.72-2.79 (1H, m), 2.88(3H, br s), 2.99-3.07 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.67-3.73(1H, m), 4.08-4.13 (1H, m), 4.28-4.31 (1H, m), 6.81 (2H, d, J=9.2 Hz),7.24 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=9.2 Hz).

MS (EI) m/z: 387 (M)⁺.

EXAMPLE 90 4-(3-(4-Chloro-3-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-116)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-chloro-3-nitrophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.51 (3H, s), 2.59-2.67 (1H, m),2.97-3.10 (1H, m), 3.01 (3H, s), 3.10 (3H, s), 3.67-3.73 (1H, m),4.02-4.07 (1H, m), 4.28-4.31 (1H, m), 6.98 (1H, dd, J=8.9 Hz, 3.0 Hz),7.21 (2H, d, J=8.5 Hz), 7.28 (1H, d, J=3.0 Hz), 7.39 (1H, d, J=8.9 Hz),7.59 (2H, d, J=8.5 Hz)

MS (FAB) m/z: 408 (M+H)⁺.

EXAMPLE 91 4-[1-Methylamino-3-(2,3,5-trifluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-118)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2,3,5-trifluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54 (3H, s), 2.62-2.68 (1H, m), 3.02(3H, s), 3.02-3.11 (1H, m), 3.11 (3H, s), 3.62-3.66 (1H, m), 4.09-4.12(1H, m), 4.35-4.38 (1H, m), 6.35-6.39 (1H, m), 6.49-6.54 (1H, m), 7.22(2H, d, J=8.3 Hz), 7.65 (2H, d, J=8.3 Hz)

MS (FAB) m/z: 383 (M+H)⁺.

EXAMPLE 92 4-[3-(3-Fluorophenylamino)-1-methylaminopropyl]phenyldimethylcarbamate dihydrochloride (Exemplification Compound Number 1-51)

t-Butyl (3-fluorophenyl)carbamate was treated using similar proceduresto those described in Example 87 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.46 (3H, s), 2.76-2.82 (1H, m), 3.01(3H, s), 3.10 (3H, s), 3.20-3.26 (1H, m), 3.34-3.45 (2H, m), 4.07-4.13(1H, m), 7.06-7.11 (1H, m), 7.24-7.26 (1H, m), 7.30-7.42 (4H, m), 7.64(2H, br s).

MS (FAB) m/z: 346 (M+H)⁺.

EXAMPLE 93 4-[2-(4-Chlorophenoxy)-1-methylaminoethyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-34)(a) 2-(4-Chlorophenoxy)-1-[(4-methoxymethoxy)phenyl]ethanone

1-Iodo-4-methoxymethoxybenzene (1.72 g, 6.5 mmol), which was synthesizedaccording to the method described in Chem. Abstr., 68, 87026, (1968),was dissolved in tetrahydrofuran (40 ml) and 1.5N solution of butyllithium in hexane (4.3 ml, 6.5 mmol) was added dropwise to the solutionat −78° C. The resulting mixture was stirred for 30 minutes and then tothe mixture was added a solution of2-(4-chlorophenoxy)-N-methoxy-N-methylacetamide (1.00 g, 4.4 mmol),which was synthesized according to the method described in Tetrahedron,54, 15861, (1998), in tetrahydrofuran. The mixture was stirred for 2hours and the reaction mixture was partitioned between saturated aqueoussodium chloride solution and ether. The organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column usinghexane:ethyl acetate=95:5 to 80:20 as the eluent to afford the desiredcompound (1.02 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 3.49 (3H, s), 5.20 (2H, s), 5.25 (2H, s),6.87 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=8.9 Hz), 7.23 (2H, d, J=9.0 Hz),7.97 (2H, d, J=8.9 Hz).

(b) 2-(4-Chlorophenoxy)-1-(4-hydroxyphenyl)ethanone

2-(4-Chlorophenoxy)-1-[(4-methoxymethoxy)phenyl]ethanone (1.01 g, 3.3mmol) obtained from Example 93a was dissolved in acetone (10 ml) and tothe solution was added 4N aqueous hydrochloric acid solution (10 ml).The resulting mixture was stirred at room temperature overnight and thereaction mixture was neutralized with saturated aqueous sodiumhydrogencarbonate solution. The mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure to afford the crude desiredcompound (0.85 g) which was used in next step reaction without furtherpurification.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 5.34 (2H, s), 6.63 (1H, s), 6.89 (2H, d,J=8.8 Hz), 6.93 (2H, d, J=9.1 Hz), 7.24 (2H, d, J=9.1 Hz), 7.94 (2H, d,J=8.8 Hz)

(c) 4-[2-(4-Chlorophenoxy)-1-methylaminoethyl]phenyl dimethylcarbamatehydrochloride

2-(4-Chlorophenoxy)-1-(4-hydroxyphenyl)ethanone obtained in Example 93bwas treated using similar procedures to those described in Example 1a,and 1d to 1f, to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.36 (3H, s), 3.02 (3H, s), 3.11 (3H, s),4.27-4.36 (2H, m), 4.60 (1H, dd, J=11.3 Hz, 9.2 Hz), 6.96 (2H, d, J=8.9Hz), 7.16 (2H, d, J=8.9 Hz), 7.21 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.6Hz), 10.21 (2H, br s).

MS(FAB) m/z: 349 (M+H)⁺

EXAMPLE 94 3-[3-(3- Fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-76)

3-Fluorophenol was treated using similar procedures to those describedin Example 7f and 7g to afford the title compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.41-2.61 (1H, m), 2.53 (3H, br s),2.90-3.02 (1H, m), 2.99 (3H, s), 3.08 (3H, s), 3.59-3.65 (1H, m),3.94-3.99 (1H, m), 4.32 (1H, br s), 6.51 (1H, dt, J=11.2 Hz, 2.2 Hz),6.57-6.64 (2H, m), 7.13-7.20 (2H, m), 7.33(1H, s), 7.41-7.47 (2H, m),9.94 (1H, br s), 10.36 (1H, br s).

MS(FAB) m/z: 347 (M+H)⁺.

EXAMPLE 95 3-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-92)

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 7e was treated using similar procedures to thosedescribed in Example 48 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54 (3H, s), 2.65-2.70 (1H, m), 2.98(3H, s), 3.01-3.10 (1H, m), 3.07 (3H, s), 3.75-3.81 (1H, m), 4.08-4.13(1H, m), 4.30 (1H, dd, J=9.9 Hz, 4.1 Hz), 6.87 (2H, d, J=9.3 Hz),7.17-7.21 (1H, m), 7.31 (1H, s), 7.43-7.48 (2H, m), 8.15 (2H, d, J=9.3Hz), 10.05 (1H, br s), 10.48 (1H, br s).

MS(FAB) m/z: 374 (M+H)⁺.

EXAMPLE 96 4-[3-(2-Fluoro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-105)

2-Fluoro-4-nitrophenol was treated using similar procedures to thosedescribed in Example 48 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53 (3H, s), 2.66-2.74 (1H, m), 3.01(3H, s), 3.05-3.14 (1H, m), 3.09 (3H, s), 3.76-3.82 (1H, m), 4.21-4.26(1H, m), 4.34-4.37 (1H, m), 6.88 (1H, t, J=8.7 Hz), 7.21 (2H, d, J=8.6Hz), 7.63 (2H, d, J=8.6 Hz), 7.95-8.00 (2H, m).

MS (FAB) m/z: 392 (M+H)⁺.

EXAMPLE 97 4-[3-(4-Fluorophenylamino)-1-methylaminopropyl]phenyldimethylcarbamate dihydrochloride (Exemplification Compound Number 1-49)

t-Butyl (4-fluorophenyl)carbamate was treated using similar proceduresto those described in Example 87 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.46 (3H, s), 2.72-2.77 (1H, m), 3.01(3H, s), 3.09 (3H, s), 3.17-3.22 (1H, m), 3.38-3.49 (2H, m), 4.01-4.09(1H, br s), 7.10 (2H, t, J=8.4 Hz), 7.24-4.26 (2H, m), 7.62-7.65 (4H,m).

EXAMPLE 98 (S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-92)(a) t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamate

t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 81a and 4-nitrophenol were treated using a similarprocedure to that described in Example 48a to afford the desiredcompound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.40 (9H, s), 2.17-2.40 (2H, m), 3.01(3H, s), 3.10 (3H, s), 3.96-4.10 (2H, m), 4.90-5.01 (2H, br s), 6.91(2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 8.19(2H, d, J=8.8 Hz).

(b) (S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride

t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamateobtained from Example 98a was treated using similar procedures to thosedescribed in Example 61d and 61e to afford the title compound.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.62-2.66 (1H, m), 3.01(3H, s), 3.01-3.10 (1H, m), 3.10 (3H, s), 3.72-3.75 (1H, m), 4.07-4.11(1H, m), 4.29-4.32 (1H, m), 6.86 (2H, d, J=9.2 Hz), 7.20 (2H, d, J=8.4Hz), 7.59 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=9.2 Hz).

[α]_(D) ²²+143.6, (CHCl₃, C=1.01)

MS(FAB) m/z: 374 (M+H)⁺.

EXAMPLE 99 (S)-4-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-149)

(S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamateobtained from Example 98 was treated using a similar procedure to thatdescribed in Example 3 to give the desired product, which wasrecrystallized from a mixture of ethyl acetate and hexane to afford thetitle compound as crystals (mp 180.5-181.5° C.)

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.62 (3H, br s), 2.72-2.79 (1H, m), 2.88(3H, br s), 2.99-3.07 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.67-3.73(1H, m), 4.08-4.13 (1H, m), 4.28-4.31 (1H, m), 6.81 (2H, d, J=9.2 Hz),7.24 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=9.2 Hz).

[α]_(D) ²²+116.0(CHCl₃, C=0.94)

MS(EI) m/z: 387 (M)⁺.

EXAMPLE 100 (R)-4-[1-Amino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-66)(a) t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamate

t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 61b and 4-nitrophenol were treated using a similarprocedure to that described in Example 48a to afford the desiredcompound.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.40 (9H, s), 2.18-2.40 (2H, m), 3.01 (3H,s), 3.09 (3H, s), 3.99 (1H, dt, J=6.2, 9.6 Hz), 4.08 (1H, dt, J=6.2, 9.6Hz), 4.85-5.03 (2H, br), 6:91 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8 Hz),7.27 (2H, d, J=8.8 Hz), 8.18 (2H, d, J=8.8 Hz).

(b) (R)-4-[1-Amino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamatehydrochloride

t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamateobtained from Example 100a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.36-2.46 (1H, m), 2.66-2.75 (1H, m),2.95 (3H, s), 3.07 (3H, s), 3.81-3.89 (1H, m), 4.06-4.14 (1H, m), 4.46(1H, dt, J=5.6 Hz, 3.2 Hz), 6.87 (2H, d, J=9.6 Hz), 7.06 (2H, d, J=8.8Hz), 7.52 (2H, d, J=8.8 Hz), 8.14 (2H, d, J=9.6 Hz).

[α]_(D) ²²−110.5(CHCl₃, C=1.04)

MS(FAB) m/z: 360 (M+H)⁺.

EXAMPLE 101 (R)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-92)

t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamateobtained from Example 100a was treated using similar procedures to thosedescribed in Example 61d and 61e to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H;s), 2.62-2.66 (1H, m), 3.01 (3H,s), 3.01-3.10 (1H, m), 3.10 (3H, s), 3.72-3.75 (1H, m), 4.07-4.11 (1H,m), 4.29-4.32 (1H, m), 6.86 (2H, d, J=9.2 Hz), 7.20 (2H, d, J=8.4 Hz),7.59 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=9.2 Hz).

[α]_(D) ²²−142.1(CHCl₃, C=1.00)

MS(FAB) m/z: 374 (M+H)⁺.

EXAMPLE 102 (R)-4-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-149)

(R)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamateobtained from Example 101 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.62 (3H, br s), 2.72-2.79 (1H, m), 2.88(3H, br s), 2.99-3.07 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.67-3.73(1H, m), 4.08-4.13 (1H, m), 4.28-4.31 (1H, m), 6.81 (2H, d, J=9.2 Hz),7.24 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz), 8.15 (2H, d, J=9.2 Hz).

[α]_(D) ²²−115.2(CHCl₃, C=0.92)

MS(EI) m/z: 387 (M+H)⁺.

EXAMPLE 103 4-[1-Methylamino-3-(pyridin-3-yloxy)propyl]phenyldimethylcarbamate dihydrochloride (Exemplification Compound Number1-119)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 3-hydroxypyridine were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.45-2.56 (1H, m), 2.58 (3H, s),2.65-3.73 (1H, m), 3.07 (3H, s), 3.99-4.04 (1H, m), 4.21-4.26 (1H, m),4.49 (1H, dd, J=10.4 Hz, 4.4 Hz), 7.19 (2H, d, J=8.8 Hz), 7.48 (2H, d,J=8.8 Hz), 7.85-7.89 (1H, m), 8.00 (1H, d, J=7.2 Hz), 8.37 (1H, d, J=6.0Hz), 8.39 (1H, a).

EXAMPLE 104 3-[1-Dimethylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-149)

3-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamateobtained from Example 95 was treated using a similar procedure to thatdescribed in Example 3 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.53-2.9 (7H, m), 3.00 (3H, s), 2.98-3.12(1H, m), 3.09 (3H, s), 3.75-3.81 (1H, m), 4.10-4.15 (1H, m), 4.34 (1H,dd, J=11.0 Hz, 3.7 Hz), 6.82 (2H, d, J=8.8 Hz), 7.24 (1H, d, J=7.7 Hz),7.3 (1H, s), 7.36 (1H, d, J=7.7 Hz), 7.46(1H, t, J=7.7 Hz), 8.14 (2H, d,J=8.8 Hz).

MS(FAB) m/z: 388 (M+H)⁺.

EXAMPLE 105 4-[1-Ethylamino-3-(3-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-70)(a) t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamate

4-Hydroxybenzaldehyde and ethylamine acetate were treated using similarprocedures to those described in Example 7a to 7e to afford the desiredcompound.

(b) 4-[1-Ethylamino-3-(3-nitrophenoxy)propyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamateobtained from Example 105a and 3-nitrophenol were treated similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.46 (3H, t, J=7.3 Hz), 2.67-2.75 (1H,m), 2.82-2.90 (1H, m), 2.93 (3H, s), 3.05-3.19 (1H, m), 3.09 (3H, s),3.64-3.70 (1H, m), 4.00-4.05 (1H, m), 4.42 (1H, dd, J=10.7 Hz, 3.4 Hz),7.12 (1H, dd, J=8.2 Hz, 2.0 Hz), 7.19 (2H, d, J=8.6 Hz), 7.38 (1H, t,J=8.2 Hz), 7.56 (1H, t, J=2.0 Hz), 7.65 (2H, d, J=8.6 Hz), 7.78 (1H, dd,J=8.2 Hz, 2.0 Hz), 9.95 (1H, br s), 10.28 (1H, br s).

MS(FAB) m/z: 388 (M+H)⁺.

EXAMPLE 106 4-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-67)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamateobtained from Example 105a and 4-fluorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.46 (3H, t, J=7.0 Hz), 2.56-2.66 (1H,m), 2.79-2.92(2H, m), 3.01 (3H, s), 3.00-3.10(1H, m), 3.09 (3H, s),3.49-3.54 (1H, m), 3.84-3.89 (1H, m), 4.43 (1H, d, J=8.1 Hz), 6.67-6.70(2H, m), 6.87-6.91 (2H, m), 7.18 (2H, d, J=8.4 Hz), 7.65 (2H, d, J=8.4Hz), 9.92 (1H, br s), 10.21 (1H, br s).

MS(FAB) m/z: 361 (M+H)⁺.

EXAMPLE 107 4-[1-Ethylamino-3-(3-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-68)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamateobtained from Example 105a and 3-fluorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.45 (3H, t, J=7.3 Hz), 2.60-2.70 (1H,m), 2.83-2.93 (2H, m), 3.01 (3H, s), 3.01-3.13 (1H, m), 3.09 (3H, s),3.50-3.56 (1H, m), 3.87-3.92 (1H, m), 4.42 (1H, brd, J=8.1 Hz), 6.47(1H, dt, J=11.0 Hz, 2.2 Hz), 6.54 (1H, dd, J=8.1 Hz, 2.2 Hz), 6.60 (1H,td, J=8.1 Hz, 2.2 Hz), 7.13 (1H, dd, J=8.1 Hz, 6.6 Hz), 7.18 (2H, d,J=8.4 Hz), 7.65 (2H, d, J=8.4 Hz), 9.95 (1H, br s), 10.26 (1H, br s)

MS(FAB) m/z: 361 (M+H)⁺.

EXAMPLE 108 3-[1-Methylamino-3-(3-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 2-94)

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 7e and 3-nitrophenol were treated using similarprocedures to those described in Example 48 to afford the title compoundas an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.25 (3H, s), 2.61-2.69 (1H, m), 2.98(3H, s), 2.97-3.10 (1H, m), 3.08 (3H, s), 3.73-3.79 (1H, m), 4.07-4.12(1H, m), 4.35 (1H, dd, J=10.3 Hz, 4.4 Hz), 7.14-7.20 (2H, m), 7.35-7.48(4H, m), 7.60 (1H, t, J=2.0 Hz), 7.79 (1H, dd, J=8.1 Hz, 2.2 Hz), 10.10(2H, br)

MS(FAB) m/z: 374 (M+H)⁺.

EXAMPLE 109 4-[3-(4-Chlorophenylamino)-1-methylaminopropyl]phenyldimethylcarbamate dihydrochloride (Exemplification Compound Number 1-50)

t-Butyl (4-chlorophenyl)carbamate was treated using similar proceduresto those described in Example 87 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.46 (3H, s), 2.71-2.76 (1H, m), 3.01(3H, s), 3.09 (3H, s), 3.16-3.23 (1H, m), 3.38-3.49 (2H, m), 4.05-4.08(1H, m), 7.23-7.26 (2H, m), 7.39 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8Hz), 7.63 (2H, br s).

MS (FAB) m/z: 362 (M+H)⁺.

EXAMPLE 1104-[3-[N-Acetyl-N-(3-chlorophenyl)amino]-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-60)

N-(3-Fluorophenyl)acetamide was treated using similar procedures tothose described in Example 87 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.94 (3H, s), 2.10-2.15 (1H, m), 2.45(3H, s), 2.71-2.77 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.58-3.63 (1H,m), 3.91-3.95 (1H, m), 4.13-4.18 (1H, m), 6.99 (1H, d, J=8.1 Hz),7.08-7.14 (2H, m), 7.20 (2H, d, J=8.0 Hz), 7.41-7.47 (1H, m), 7.69 (2H,d, J=8.0 Hz).

MS (EI) m/z: 387 (M)⁺.

EXAMPLE 111 4-[1-Methylamino-3-(3-methyl-4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-115)

3-Methyl-4-nitrophenol was treated using similar procedures to thosedescribed in Example 48 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.52 (3H, s), 2.58 (3H, s), 2.58-2.66(1H, m), 3.01 (3H, s), 3.01-3.10 (1H, m), 3.10 (3H, s), 3.67-3.73 (1H,m), 4.03-4.07 (1H, m), 4.29-4.34 (1H, m), 6.68-6.70 (2H, m), 7.20 (2H,d, J=8.3 Hz), 7.59 (2H, d, J=8.3 Hz), 8.01 (1H, d, J=9.1 Hz)

MS (FAB) m/z: 388 (M+H)⁺.

EXAMPLE 112 4-(1-Methylamino-3-o-toluyloxypropyl)phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-84)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-methylphenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.21. (3H, s), 2.52 (3H, s), 2.57-2.63(1H, m), 2.95-3.09 (1H, m),-3.00 (3H, s), 3.09 (3H, s), 3.59-3.65 (1H,m), 3.96-4.00 (1H, m), 4.30-4.36 (1H, m), 6.61 (1H, d, J=8.1 Hz), 6.82(1H, t, J=8.1 Hz), 7.03-7.11 (2H, m), 7.18 (2H, d, J=8.0 Hz), 7.61 (2H,d, J=8.0 Hz).

MS (EI) m/z: 342 (M)⁺.

EXAMPLE 113 4-[3-(4-Chloro-2-methylphenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-112)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-chloro-2-methylphenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.17 (3H, s), 2.51 (3H, t, J=2.7 Hz),2.56-2.63 (1H, m), 2.94-3.09 (1H, m), 3.01 (3H, s), 3.09 (3H, s),3.57-3.63 (1H, m), 3.92-3.97 (1H, m), 4.27-4.32 (1H, m), 6.52 (1H, d,J=8.7 Hz), 7.01 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.07 (1H, d, J=2.5 Hz), 7.19(2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz).

MS (EI) m/z: 376 (M)⁺.

EXAMPLE 114 4-[1-Dimethylamino-3-(3,4,5-trifluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-174)

4-[1-Methylamino-3-(3,4,5-trifluorophenoxy)propyl]phenyldimethylcarbamate obtained from Example 80 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.60 (3H, d, J=5.0 Hz), 2.65-2.74 (1H,m), 2.88 (3H, d, J=4.7 Hz), 2.91-3.02 (1H, m), 3.02 (3H, s), 3.11 (3H,s), 3.48 (1H, td, J=9.6 Hz, 3.6 Hz), 3.89-3.95 (1H, m), 4.21-4.28 (1H,m), 6.34-6.39 (2H, m), 7.24(2H, d, J=8.5 Hz), 7.55 (2H, d, J=8.5 Hz).

MS(EI) m/z: 396 (M+H)⁺

EXAMPLE 115 4-[4-(4-Chlorophenoxy)-1-methylaminobutyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-193)(a) Ethyl3-(4-benzyloxyphenyl)-3-[N-(t-butoxycarbonyl)-N-methylamino]propionate

N,N-Dimethylformamide and benzyl bromide (2.3 ml, 19 mmol) were addedsequentially to ethyl 3-[N-(t-butoxycarbonyl)-N-methylamino]-3-(4-hydroxyphenyl)propionate (5.10 g, 16 mmol)obtained from Example 16a and potassium carbonate (3.27 g, 24 mmol) andthe mixture was stirred at room temperature for 4 hours. The reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with water and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel column to afford the desired compound (5.57 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.23 (3H, t, J=7.2 Hz), 1.48 (9H, s),2.61 (3H. br s), 2.88-2.92 (2H, m), 4.21 (2H, q, J=7.2 Hz), 5.05 (2H,s), 5.66 (1H, br s), 6.94 (2H, d, J=8.4 Hz), 7.18 (2H, d, J=8.4 Hz),7.31-7.44 (5H, m).

(b) t-Butyl N-[1-(4-benzyloxyphenyl)-3-hydroxypropyl]-N-methylcarbamate

Tetrahydrofuran (100 ml) was added to lithium aluminum hydride (1.02 g,27 mmol) under an atmosphere of nitrogen, and a solution of ethyl3-(4-benzyloxyphenyl)-3-[N-(t-butoxycarbonyl)-N-methylamino]propionate(5.56 g, 13 mmol) obtained from Example 115a in tetrahydrofuran wasslowly added thereto at −78° C. After stirring the resulting mixture for30 minutes, the temperature was gradually raised to 0° C. and then themixture was stirred for 30 minutes. To the reaction mixture was addedsequentially water (1 ml), 15% aqueous sodium hydroxide solution (1 ml)and water (3 ml) and the resulting mixture was stirred at roomtemperature for 30 minutes. To the mixture was added anhydrous magnesiumsulfate and the resulting mixture was filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column to afford the desired compound(4.78 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.51 (9H, s), 1.92-2.15 (2H, m), 2.42(3H, br s), 3.50-3.74 (3H, m), 5.06 (2H, s), 5.54 (1H, br s), 6.95 (2H,d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 7.31-7.45 (5H, m).

(c) t-Butyl N-[1-(4-benzyloxyphenyl)-3-cyanopropyl]-N-methylcarbamate

t-Butyl N-[1-(4-benzyloxyphenyl)-3-hydroxypropyl]-N-methylcarbamate(1.50 g, 4.0 mmol) obtained from Example 115b was dissolved intetrahydrofuran (20 ml) under an atmosphere of nitrogen. To the solutionwas added triethylamine (0.84 ml, 6.0 mmol) and then methanesulfonylchloride (0.37 ml, 4.8 mmol), in an ice bath. The resulting mixture wasstirred at room temperature for 30 minutes. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (20 ml) and to thesolution was added 15-crown-5 (1.2 ml, 6.0 mmol) and then sodium cyanide(294 mg, 6.0 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenwater and ethyl acetate. The organic layer was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bychromatography on a silica gel column using hexane ethyl acetate=80:20to 70:30 as the eluent to afford the desired compound (1.41 g).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.51 (9H, br s), 2.20-2.28 (1H, m), 2.41(3H, br s), 5.06 (2H, s), 5.35 (1H, br s), 6.96 (2H, d, J=8.6 Hz), 7.17(2H, d, J=8.6 Hz), 7.31-7.44 (5H, m).

(d) t-Butyl N-[1-(4-benzyloxyphenyl)-4-hydroxybutyl]-N-methylcarbamate

t-Butyl N-[1-(4-benzyloxyphenyl)-3-cyanopropyl]-N-methylcarbamate (1.00g, 2.6 mmol) obtained from Example 115c was dissolved in dichloromethane(20 ml) under an atmosphere of nitrogen. To the solution was added 0.95M solution of diisobutylaluminum hydride in hexane (5.5 ml, 5.3 mmol) at−78° C. and the temperature was slowly raised to room temperature andthen the mixture was stirred at room temperature for 2 hours. To theresulting mixture was added sodium sulfate (2.6 g) and this mixture wasstirred at room temperature for 1 hour. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in methanol (10 ml) and to the solution was slowlyadded sodium borohydride (98 mg, 2.6 mmol). The resulting mixture wasstirred at room temperature for 1 hour. Water was added to the reactionmixture and the methanol was evaporated under reduced pressure. Theaqueous layer was extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by chromatography on a silica gelcolumn using hexane:ethyl acetate=70:30 to 50:50 as the eluent to affordthe desired compound (830 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.49 (9H, s), 1.59-1.65 (2H, m),1.89-2.01 (2H, m), 2.53 (3H, br s), 3.73 (2H, t, J=6.2 Hz), 5.05 (2H,s), 5.20 (0.5H, br s), 5.39 (0.5H, br s), 6.94 (2H, d, J=8.5 Hz), 7.21(2H, d, J=8.5 Hz), 7.31-7.44 (5H, m).

(e) t-Butyl N-[4-hydroxybutyl-1-(4-hydroxyphenyl)]-N-methylcarbamate

t-Butyl N-[1-(4-benzyloxyphenyl)-4-hydroxybutyl]-N-methylcarbamate (278mg, 0.72 mmol) obtained from Example 126d was dissolved in methanol (5ml) and to the solution was added 5% palladium on charcoal (30 mg). Themixture was stirred under an atmosphere of hydrogen at room temperaturefor 2 hours. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure to afford the crude desiredcompound, which was used in the reaction of the next step withoutfurther purification.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.49 (9H, s), 1.54-1.67 (2H, m),1.87-2.06 (2H, m), 2.54 (3H, br s), 3.01 (3H, s), 3.10 (3H, s), 3.73(2H, t, J=6.2 Hz), 5.22 (0.5H, br s), 5.43 (0.5H, br s), 7.07 (2H, d,J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz).

(f) t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl[-4-hydroxybutyl]-N-methylcarbamate

The crude product of t-butylN-[4-hydroxybutyl-1-(4-hydroxyphenyl)]-N-methylcarbamate obtained fromExample 126e and potassium carbonate (150 mg, 1.1 mmol) were dissolvedin N,N-dimethylformamide (5 ml) under an atmosphere of nitrogen. To thesolution was added dimethylcarbamyl chloride (0.079 ml, 0.86 mmol) andthe resulting mixture was stirred at room temperature overnight. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with water and saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography on a silica gel column to afford the desired compound(220 mg).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.48 (9H, s), 1.80-1.84 (2H, m),1.99-2.10 (2H, m), 2.56 (3H, br s), 3.01 (3H, s), 3.10 (3H, s), 4.00(2H, t, J=6.1 Hz), 5.24 (0.5H, br s), 5.45 (0.5H, br s), 6.82 (2H, d,J=8.9 Hz), 7.08 (2H, d, J=8.6 Hz), 7.23 (2H, d, J=8.9 Hz), 7.28 (2H, d,J=8.6 Hz).

(g) 4-[4-(4-Chlorophenoxy)-1-methylaminobutyl]phenyl dimethylcarbamatehydrochloride

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-4-hydroxybutyl]-N-methylcarbamateobtained from Example 115f and 4-chlorophenol were treated using similarprocedures to those described in Example 7f and 7g to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.52-1.76 (2H, m), 2.30-2.42 (1H, m),2.43 (3H, s), 2.47-2.63 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.81 (2H!t,J=6.1 Hz), 4.00 (1H, dd, J=10.5 Hz, 4.3 Hz), 6.72 (2H, d, J=9.0 Hz),7.17 (2H, d, J=9.0 Hz), 7.21 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.6 Hz),9.86 (1H, br s), 10.16 (1H, br s).

MS(FAB) m/z: 377 (M+H)⁺

EXAMPLE 116 4-[1-Methylamino-4-(4-nitrophenoxy)butyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-194)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-4-hydroxybutyl]-N-methylcarbamateobtained from Example 115f was treated using similar procedures to thosedescribed in Example 48 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.53-1.83 (2H, m), 2.32-2.45 (1H, m),2.44 (3H, s), 2.55-2.65 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 3.94 (2H,t, J=6.0 Hz), 4.00 (1H, br s), 6.85 (2H, d, J=9.1 Hz), 7.21 (2H, d,J=8.4 Hz), 7.58 (2H, d, J=8.4 Hz), 8.14 (2H, d, J=9.1 Hz), 9.86 (1H, brs), 10.21 (1H, br s).

MS(FAB) m/z: 388 (M+H)⁺

EXAMPLE 117 4-[[1-Methylamino-2-(4-nitrophenoxy)ethyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-39)

N-Methoxy-N-methyl-2-(4-nitrophenoxy)acetamide was treated using similarprocedures to those described in Example 93 to afford the title compoundas an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.34 (3H, s), 3.03 (3H, s), 3.12 (3H, s),4.37 (1H, br s), 4.48 (1H, dd, J=10.0 Hz, 4.2 Hz), 4.74 (1H, dd, J=10.0Hz, 7.9 Hz), 7.13 (2H, d, J=9.2 Hz), 7.23 (2H, d, J=8.5 Hz), 7.67 (2H,d, J=8.5 Hz), 8.13 (2H, d, J=9.2 Hz), 10.33 (2H, br s).

MS(FAB) m/z: 360 (M+H)⁺

EXAMPLE 1184-[3-[N-Acetyl-N-(4-chlorophenyl)amino]-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-59)

N-(4-Chlorophenyl)acetamide was treated using similar procedures tothose described in Example 87 to afford the title compound as anamorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.90 (3H, s), 2.12-2.18 (1H, m), 2.43(3H, t, J=2.6 Hz), 2.66-2.73 (1H, m), 3.02 (3H, s), 3.11 (3H, s),3.61-3.67 (1H, m), 3.95-3.97 (1H, m), 4.02-4.08 (1H, m), 7.19-7.23 (4H,m), 7.42 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.5 Hz).

MS (FAB) m/z: 404 (M+H)⁺.

EXAMPLE 1194-[3-[N-Acetyl-N-(4-nitrophenyl)amino]-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification Compound Number 1-61)

N-(4-Nitrophenyl)acetamide was treated using similar procedures to thosedescribed in Example 87 to afford the title compound as an amorphoussolid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.94 (3H, s), 2.22-2.26 (1H, m), 2.44(3H, t, J=2.6 Hz), 2.68-2.86 (1H, m), 3.02 (3H, s), 3.11 (3H, s),3.77-3.83 (1H, m), 3.97-4.05 (2H, m), 7.20 (2H, d, J=8.6 Hz), 7.50 (2H,d, J=8.8 Hz), 7.63 (2H, d, J=8.6 Hz), 8.31 (2H, d, J=8.8 Hz).

MS (FAB) m/z: 415 (M+H)⁺.

EXAMPLE 120 4-[1-Methylamino-3-(4-nitrophenylamino)propyl]phenyldimethylcarbamate dihydrochloride (Exemplification compound number 1-53)

t-Butyl (4-nitrophenyl)carbamate was treated using similar procedures tothose described in Example 87 to afford the title compound as anamorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.47 (3H,s), 2.74 (1H,br s), 2.88 (1H,brs), 3.02 (3H,s), 3.11 (3H,s), 3.18 (1H,br s), 4.13 (1H,br s), 6.82(2H,br s), 7.19-7.24 (2H,m), 7.57 (2H,br s), 8.10 (2H,d,J=6.8 Hz).

MS (FAB) m/z: 373 (M+H)⁺.

EXAMPLE 121 (S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate 1/2 fumarate (Exemplification compound number 1-92)

(S)-4-[1-Methylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamateobtained from Example 98 was converted into the 1/2 fumarate thereof,which was recrystallized from isopropanol to afford the title compopundas crystals (mp 164-166° C.).

¹H-NMR(500 MHz,CD₃OD) δ ppm: 2.32-2.39 (1H,m), 2.48 (3H,s), 2.57-2.64(1H,m), 2.99 (3H,s), 3.11 (3H,s), 3.88 (1H,dt,J=9.5 Hz,5.0 Hz), 4.13(1H,dt,J=10.5 Hz,5.0 Hz), 4.30 (1H,dd,J=10.0 Hz,4.0 Hz), 6.68 (1H,s),6.99 (2H,d,J=9.3 Hz), 7.19 (2H,d,J=8.8 Hz), 7.46 (2H,d,J=8.8 Hz), 8.17(2H,d,J=9.3 Hz).

IR(KBr) ν_(max)cm⁻¹: 3423, 3108, 1717, 1591, 1511, 1389, 1341, 1257,1216, 1175, 1110, 859, 753.

Elemental analysis: Calcd for C₂₁H₂₅N₃O₇: C, 58.46; H, 5.84; N, 9.74; O,25.96. Found: C, 58.19; H, 5.68; N, 9.69; O, 26.20.

[α]_(D) ²² +119.5(MeOH,C=1.00)

EXAMPLE 122 4-[1-Methylamino-3-(4-nitrophenyl)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-19)

2-Nitrobenzaldehyde was treated using similar procedures to thosedescribed in Example 1 to afford the title compound as an amorphoussolid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.38 (3H,s), 2.51-2.58 (3H,m), 2.80-2.84(1H,m), 3.03 (3H,s), 3.12 (3H,s), 3.89 (1H,br s), 7.23 (2H,d,J=8.0 Hz),7.27 (2H,d,J=8.4 Hz), 7.53 (2H,d,J=8.0 Hz), 8.08 (2H,d,J=8.4 Hz), 9.88(1H,br s), 10.24 (1H,br s).

EXAMPLE 123 (S)-4-[1-Amino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-66)

t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-(4-nitrophenoxy)propyl]carbamateobtained from Example 98a was treated using a similar procedure to thatdescribed in Example 6d to afford the title compound as an amorphoussolid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.36-2.46 (1H,m), 2.66-2.75 (1H,m), 2.95(3H,s), 3.07 (3H,s), 3.81-3.89 (1H,m), 4.06-4.14 (1H,m), 4.46(1H,dt,J=5.6 Hz,3.2 Hz), 6.87 (2H,d,J=9.6 Hz), 7.06 (2H,d,J=8.8 Hz),7.52 (2H,d,J=8.8 Hz), 8.14 (2H,d,J=9.6 Hz).

[α]_(D) ²² +111.3(CHCl₃,C=1.01)

MS(FAB) m/z: 360 (M+H)⁺.

EXAMPLE 124 4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-108)

2-Chloro-4-nitrophenol was treated using similar procedures to thosedescribed in Example 48 to afford the title compound as an amorphoussolid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.54 (3H,s), 2.66-2.73 (1H,m), 3.00 (3H,s),3.06-3.12 (1H,m), 3.09 (3H,s), 3.73-3.79 (1H,m), 4.26-4.30 (1H,m),4.37-4.41 (1H,m), 6.83 (1H,d,J=9.1 Hz), 7.19 (2H,d,J=8.6 Hz), 7.64(2H,d,J=8.6 Hz), 8.08 (1H,dd,J=9.1 Hz,2.8 Hz), 8.27 (1H,d,J=2.8 Hz).

MS (FAB) m/z: 408 (M+H)⁺.

EXAMPLE 125 (S) -3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyldimathylcarbamate hydrochloride (Exemplification compound number 2-92)(a) t-Butyl(S)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate

Methyl (S)-3-amino-3-(3-hydroxyphenyl)propionate, which was synthesizedaccording to the method described in Tetrahedron: Asymmetry, 2, 183,(1991), was treated using similar procedures to those described inExample 61a and 61b to afford the desired compound.

(b) (S)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride

t-Butyl(S)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 125a and 4-nitrophenol were treated using similarprocedures to those described in Example 7f, 61d and 61e to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54 (3H, s), 2.67 (1H, m), 2.99 (3H, s),3.05 (1H, m), 3.07 (3H, s), 3.78 (1H, m), 4.11 (1H, m), 4.30 (1H, m),6.87 (2H, d, J=9.2 Hz), 7.20 (1H, m), 7.31 (1H, s), 7.45 (2H, m), 8.15(2H, d, J=9.2 Hz), 9.97 (1H, br s), 10.48 (1H, br s),

ms (FAB) m/z: 374 ((M+H)⁺)

EXAMPLE 126 (S)-3-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-149)

(S)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride obtained from Example 125b was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.65 (3H, s), 2.74 (1H, m), 2.85 (3H, s),3.00 (3H, s), 3.07 (1H, m), 3.09 (3H, s), 3.77 (1H, m), 4.12 (1H, m),4.30 (1H, m), 6.82 (2H, d, J=9.0 Hz), 7.24 (1H, m), 7.30 (1H, m), 7.36(1H, m), 7.46 (1H, m), 8.15 (2H, d, J=9.0 Hz),

ms (FAB) m/z: 388 ((M+H)⁺)

EXAMPLE 127(S)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-108)

t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 81a and 2-chloro-4-nitrophenol were treated usingsimilar procedures to those described in Example 7f, 61d and 61e toafford the title compound as an amorphous solid.

¹H-NMR(500 MHz,CDCl₃) δ ppm 2.54 (3H,s), 2.67-2.72 (1H,m), 3.00(3H,s),3.05-3.14 (1H,m), 3.09 (3H,s), 3.73-3.77 (1H,m), 4.27-4.30(1H,m), 4.37-4.41 (1H,m), 6.83 (1H,d,J=9.0 Hz), 7.19 (2H,d,J=9.0 Hz),7.64 (2H,d,J=9.0 Hz), 8.08 (1H,dd,J=9.0 Hz,3.0 Hz), 8.27 (1H,d,J=3.0 Hz)

IR(CHCl₃) 2977, 2710, 1587, 1515, 1492, 1392, 1346, 1277, 1176, 1054,1027, 1019.

[α]_(D) ²² +135.1(CHCl₃,C=0.72)

EXAMPLE 128(R)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-108)

t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 61a and 2-chloro-4-nitrophenol were treated usingsimilar procedures to those described in Example 7f, 61d and 61e toafford the title compound as an amorphous solid.

¹H-NMR(500 MHz,CDCl₃) δ ppm: 2.54 (3H,s), 2.67-2.72 (1H,m), 3.00 (3H,s),3.05-3.14 (1H,m), 3.09 (3H,s), 3.73-3.77 (1H,m), 4.27-4.30 (1H,m),4.37-4.41 (1H,m), 6.83 (1H,d,J=9.0 Hz), 7.19 (2H,d,J=9.0 Hz), 7.64(2H,d,J=9.0 Hz), 8.08 (1H,dd,J=9.0 Hz,3.0 Hz), 8.27 (1H,d,J=3.0 Hz)

IR(CHCl₃) 2977, 2710, 1587, 1515, 1492, 1392, 1346, 1277, 1176, 1054,1027, 1019.

[α]_(D) ²² −131.0(CHCl₃,C=0.86)

EXAMPLE 129(S)-4-[3-(2-Chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-165)

(S)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 127 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR(500 MHz,CDCl₃) δ ppm: 2.61 (3H,d,J=5.0 Hz), 2.80-2.89 (1H,m),2.95 (3H,d,J=5.0 Hz), 3.01 (3H,s), 3.02-3.10 (1H,m), 3.10 (3H,s),3.66-3.74 (1H,m), 4.23-4.30 (1H,m), 4.31-4.37 (1H,m), 6.82 (1H,d,J=9.0Hz), 7.22 (2H,d,J=9.0 Hz), 7.62 (2H,d,J=9.0 Hz), 8.09 (1H,dd,J=9.0Hz,2.5 Hz), 8.27 (1H,d,J=2.5 Hz).

IR(CHCl₃) 2970, 2317, 1725, 1587, 1517, 1492, 1467, 1392, 1346, 1277,1176, 1054, 1029, 1018.

[α]_(D) ²² +142.0(CHCl₃,C=0.96)

EXAMPLE 130(R)-4-[3-(2-Chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-165)

(R)-4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 128 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR(500 MHz,CDCl₃) δ ppm: 2.61 (3H,d,J=5.0 Hz), 2.80-2.89 (1H,m),2.95 (3H,d,J=5.0 Hz), 3.01 (3H,s), 3.02-3.10 (1H,m), 3.10 (3H,s),3.66-3.74 (1H,m), 4.23-4.30 (1H,m), 4.31-4.37 (1H,m), 6.82 (1H,d,J=9.0Hz), 7.22 (2H,d,J=9.0 Hz), 7.62 (2H,d,J=9.0 Hz), 8.09 (1H,dd,J=9.0Hz,2.5 Hz), 8.27 (1H,d,J=2.5 Hz).

IR(CHCl₃) 2970, 2317, 1725, 1587, 1517, 1492, 1467, 1392, 1346, 1277,1176, 1054, 1029, 1018.

[α]_(D) ²² −141.6(CHCl₃,C=1.16)

EXAMPLE 131 4-[3-(2-Chloro-4-nitrophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-165)

4-[3-(2-Chloro-4-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 124 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.61(3H,d,J=5.1 Hz), 2.81-2.89(1H,m),2.95(3H,d J=5.1 Hz), 3.01(3H,s), 3.01-3.10(1H,m), 3.10(3H,s),3.67-3.72(1H,m), 4.26-4.33(2H,m), 6.81(1H,d,J=9.0 Hz), 7.22(2H,d,J=8.4Hz), 7.61(2H,d,J=8.4 Hz), 8.09(1H,dd,J=9.0,2.7 Hz), 8.28(1H,d,J=2.7 Hz).

IR(KBr) ν_(max)cm⁻¹: 3427, 2934, 2555, 2457, 1726, 1516.

MS m/z: 422([M+H]⁺), 406, 377, 221, 204.

EXAMPLE 132 4-[1-Methylamino-3-(5-chloropyridin-3-yloxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-120)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 5-chloropyridin-3-ol were treatedusing-similar procedures to those described in Example 7f and 7g toafford the title compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.49(3H,brs), 2.62(1H,brs), 3.02(3H,s),3.12(3H,s), 4.39(2H,br s), 4.83(1H,br s), 7.22(2H,br s), 7.67(2H,br s),7.84(1H,br s), 8.41(1H,br s), 9.05(1H,br s), 10.14(1H,br s), 10.39(1H,brs).

IR(KBr) ν_(max)cm⁻¹: 2941, 2738, 2473, 2023, 1732, 1549.

MS m/z: 364([M+H]⁺), 333, 273, 259, 242, 207.

EXAMPLE 133 4-[1-Methylamino-3-(6-methylpyridin-3-yloxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-122)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 6-methylpyridin-3-ol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.47(3H,t,J=5.2 Hz), 2.58(3H,s),2.58-2.66(1H,m), 2.83(3H,s), 3.02(3H,s), 3.02-3.11(1H,m), 3.11(3H,s),4.31-4.36(1H,m), 4.41-4.43(1H,m), 4.56-4.61(1H,m), 7.19(2H,d,J=8.5 Hz),7.53(1H,d,J=8.9 Hz), 7.68(2H,d,J=8.5 Hz), 7.80(1H,dd,J=8.9,2.0 Hz),8.57(1H,d,J=2.0 Hz), 10.23(2H,br s).

IR(KBr) ν_(max)cm⁻¹: 3427, 2937, 2682, 1739, 1555.

MS m/z: 344([M+H]⁺), 313, 273, 242, 207.

EXAMPLE 134 4-[1-Methylamino-3-(2-methylpyridin-3-yloxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-121)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 2-methylpyridin-3-ol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.47(3H,s), 2.68(1H,brs), 2.80(3H,s),3.01(3H,s), 3.01-3.09(1H,m), 3.11(3H,s), 4.21(1H,br s), 4.38(1H,br s),4.41(1H,br s), 7.22(2H,d,J=8.0 Hz), 7.68-7.69(3H,m), 7.84(1H,br s),8.25(1H,br s), 10.19(1H,br s), 10.26(1H,br s).

IR(KBr) ν_(max)cm⁻¹: 3423, 2938, 2759, 2690, 1722, 1550.

MS m/z: 344([M+H]⁺), 313, 273, 242, 207.

EXAMPLE 135 (R)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-194)(a) t-Butyl(R)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamate

Methyl (R)-3-amino-3-(3-hydroxyphenyl)propionate, which was synthesizedaccording to the method described in Tetrahedron: Asymmetry, 2, 183,(1991), was treated using similar procedures to those described inExample 61a and 61b to afford the desired compound.

(b) (R)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride

t-Butyl(R)-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 135a and 4-nitrophenol were treated using similarprocedures to those described in Example 7f, 61d and 61e to afford thetitle compound as an amorphous solid.

¹H-NMR-(400 MHz, CDCl₃) δ ppm: 2.54 (3H, s), 2.66 (1H, m), 2.99 (3H, s),3.05 (1H, m), 3.07 (3H, s), 3.79 (1H, m), 4.11 (1H, m), 4.31 (1H, m),6.87 (2H, d, J=9.2 Hz), 7.19 (1H, m), 7.32 (1H, s), 7.45 (2H, m), 8.16(2H, d, J=9.2 Hz),

ms (FAB) m/z: 374 ((M+H)⁺)

EXAMPLE 136 (R)-3-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-149)

(R)-3-[3-(4-Nitrophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride obtained from Example 135 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.66 (3H, m), 2.73 (1H, m), 2.86 (3H, m),3.00 (3H, s), 3.07 (1H, m), 3.09 (3H, m), 3.78 (1H, m), 4.13 (1H, m),4.34 (1H, m), 6.82 (2H, J=9.2 Hz), 7.24 (1H, dd, J=8.1 Hz, 1.5 Hz), 7.31(1H, s), 7.37 (1H, d, J=8.1), 7.46 (1H, t, J=8.l), 8.14 (2H, J=9.2),

ms (FAB) m/z: 388 ((M+H)⁺)

EXAMPLE 137 4-[1-Ethylamino-3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-71)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamateobtained from Example 105a and 4-nitrophenol were treated using similarprocedures to those described in Example 48a and 48b to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 1.46 (3H, t, J=7.3 Hz), 2.71 (1H, m), 2.88(2H, m), 3.01 (3H, s), 3.10 (3H, s), 3.14 (1H, m), 3.70 (1H, m), 4.04(1H, m), 4.40 (1H, m), 6.83 (2H, d, J=9.5 Hz), 7.19 (2H, d, J=8.8 Hz),7.63 (2H, d, J=8.8 Hz), 8.14 (2H, d, J=9.5 Hz),

ms (FAB) m/z: 388 ((M+H)⁺)

EXAMPLE 138 4-[1-Ethylamino 3-(4-nitrophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-189)

4-[1-Ethylamino-3-(4-nitrophenoxy)propyl]phenyl dimethylcarbamatehydrochloride obtained from Example 143 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.37 (1.5H, t, J=6.8 Hz), 1.52 (1.5H, t,J=6.8 Hz), 2.63 (3H, d, J=3.4 Hz), 2.76 (2H, m), 2.93 (3H, d, J=3.4 Hz),3.02 (3H, s), 3.04 (1H, m), 3.11 (3H, s), 3.27 (0.5H, m), 3.39 (0.5H,m), 3.77 (0.5H, m), 3.78 (0.5H, m), 4.11 (1H, m), 4.40 (0.5H, m), 4.54(0.5H, m), 6.81 (2H, d, J=8.8 Hz), 7.22 (2H, m), 7.56 (1H, dd, J=8.8Hz), 7.64 (1H, dd, J=7.8 Hz), 8.13 (2H, d, J=8.8 Hz),

ms (FAB) m/Z: 402 ((M+H)⁺)

EXAMPLE 139 4-[1-Ethylamino-3-(4-chlorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-69)

t-ButylN-1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamateobtained from Example 105a and 4-chlorophenol were treated using similarprocedures to those described in Example 48a and 48b to afford the titlecompound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.44 (3H, t, J=7.3 Hz), 2.63 (1H, m),2.89 (2H, m), 3.01 (3H, s), 3.08 (1H, m), 3.09 (3H, s), 3.52 (1H, m),3.88 (1H, m), 4.43 (1H, m), 6.69 (2H, m), 7.17 (4H, m), 7.63 (2H, m),

ms (FAB) m/z: 377 ((M+H)⁺)

EXAMPLE 140 4-[1-Ethylamino-3-(4-chlorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-190)

4-[1-Ethylamino-3-(4-chlorophenoxy)propyl]phenyl dimethylcarbamatehydrochloride obtained from Example 139 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.51 (1.5H, m), 1.34 (1.5H, m), 2.58 (3H,br s), 2.93 (3H, br s), 3.02 (3H, s), 3.11 (3H, s), 3.23-2.62 (4H, m),3.42 (0.5H, m), 3.53 (0.5H, m), 3.86 (0.5H, m), 3.95 (0.5H, m), 4.31(0.5H, m), 4.44 (0.5H, m), 6.67 (2H, m), 7.18 (4H, m), 7.57 (1H, d,J=7.8 Hz), 7.64 (1H, d, J=7.8 Hz)

ms (FAB) m/z: 391 ((M+H)⁺)

EXAMPLE 141 4-[1-Ethylamino-3-(3,4-difluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-72)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-ethylcarbamateobtained from Example 105a and 3,4-difluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.45 (3H, t, J=7.3 Hz), 2.62 (1H, m),2.87 (2H, m), 3.01 (3H, s), 3.08 (1H, m), 3.10 (3H, s), 3.52 (1H, m),3.87 (1H, m), 4.39 (1H, m) 6.45 (1H, m), 6.58 (1H, m), 6.99 (1H, m),7.19 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz),

ms (FAB) m/z: 379 ((M+H)⁺)

EXAMPLE 142 4-[1-Ethylmethylamino-3-(3,4-difluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-191)

4-[1-Ethylamino-3-(3,4-difluorophenoxy)propyl]phenyl dimethylcarbamatehydrochloride obtained from Example 141 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.34 (1.5H, t, J=7.3 Hz), 1.52 (1.5H, t,J=7.3 Hz), 2.57 (1.5H, d, J=4.9 Hz), 2.91 (1.5H, d, J=4.9 Hz), 3.02 (3H,d, J=2.0 Hz), 3.11 (3H, d, J=2.0 Hz), 3.56-2.65 (5H, m), 3.92 (1H, m),4.26 (0.5H, m), 4.39 (0.5H, m), 6.43 (1H, m), 6.56 (1H, m), 7.00 (1H,m), 7.21 (1H, d, J=8.8 Hz), 7.23 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=8.8Hz), 7.64 (1H, d, J=8.8 Hz),

ms (FAB) m/z: 393 ((M+H)⁺)

EXAMPLE 143 4-[1-Ethylmethylamino-3-(4-fluorophenoxy)propyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-188)

4-[1-Ethylamino-3-(4-fluorophenoxy)propyl]phenyl dimethylcarbamatehydrochloride obtained from Example 106 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.33 (1.5H, m), 1.51 (1.5H, m), 2,09(1.5H, s), 2.91 (1.5H, s), 3.02 (3H, s), 3.10 (3H, s), 3.53-2.66 (5H,m), 3.93 (1H, m), 4.27 (0.5H, m), 4.39 (0.5H, m), 6.68 (2H, dd, J=3.9Hz, 8.8 Hz), 6.91 (2H, t, J=8.8 Hz), 7.21 (2H, m), 7.56 (1H, d, J=7.8Hz), 7.66 (1H, d, J=7.8 Hz),

ms (FAB) m/z: 375 ((M+H)⁺)

EXAMPLE 144 3-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-79)

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 7e and 3-chlorophenol were treated using similarprocedures to those described in Example 48a and 48b to afford the titlecompound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.54 (3H,s), 2.56-2.62 (1H,m), 2.93-2.99(1H,m), 2.99 (3H,s), 3.08 (3H,s), 3.60-3.66 (1H,m), 3.94-3.99 (1H,m),4.29-4.33 (1H,m), 6.70 (1H,d,J=8.1 Hz), 6.79 (1H,s), 6.90 (1H,d,J=8.1Hz), 7.14 (1H,tri,J=8.1 Hz), 7.17-7.20 (1H,m), 7.33 (1H,s), 7.43-7.44(2H,m).

ms (FAB)m/z: (FAB+): 363 ((M+H)⁺)

EXAMPLE 145 3-[3-(4-Chlorophenoxy)-1-dimethylmethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-135)

3-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride obtained from Example 10 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.60-2.73 (1H,m), 2.73 (6H,br), 2.91-2.99(1H,m), 3.01 (3H,s), 3.10 (3H,s), 3.55-3.61 (1H,m), 3.96-4.00 (1H,m),4.27-4.31 (1H,m), 6.67 (2H,d,J=9.0 Hz), 7.18 (2H,d,J=9.0 Hz), 7.22(1H,dt,J=7.9 Hz,1.8 Hz), 7.30 (1H,tri,J=1.8 Hz), 7.38 (1H,d,J=7.9 Hz),7.45 (1H,tri,J=7.9 Hz)

ms(FAB)m/z: 377((M+H)⁺)

EXAMPLE 146 3-[3-(3-Chloro-4-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-109)

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 7e and 3-chloro-4-fluorophenol were treated usingsimilar procedures to those described in Example 48a and 48b to affordthe title compound as an amorphous solid.

¹H-NMR(400 MHZ,CDCl₃) δ ppm: 2.54 (3H,s), 2.56-2.62 (1H, m), 2.92-2.98(1H,m), 3.00 (3H,s), 3.09 (3H,s), 3.56-3.64 (1H,m), 3.92-3.97 (1H,m),4.28-4.32 (1H,m), 6.65-6.68 (1H,m), 6.82-6.84 (1H,m), 6.99 (1H,tri,J=8.8Hz), 7.17-7.20 (1H,m), 7.31 (1H,s), 7.44 (2H,d,J=5.1 Hz)

ms(FAB)m/z:381((M+H)⁺)

EXAMPLE 147 3-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-104)

t-ButylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 7e and 4-chloro-3-fluorophenol -were treated usingsimilar procedures to those described in Example 48a and 48b to affordthe title compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.54 (3H,s), 2.56-2.62 (1H,m), 2.93-2.98(1H,m), 2.99 (3H,s), 3.08 (3H,s), 3.60-3.65 (1H,m), 3.94-3.99 (1H,m),4.29-4.31 (1H,m), 6.56 (1H,dd,J=2.9 Hz,1.5 Hz), 6.62 (1H,dd,J=2.9 Hz,1.5Hz), 7.17-7.23 (2H,m), 7.31 (1H,m), 7.44 (2H,d,J=5.1 Hz)

ms(FAB)m/z:381((M+H)⁺)

EXAMPLE 148 3-[3-(3-Chlorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-136)

3-[3-(3-Chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamatehydrochloride obtained from Example 144 was treated using a similarprocedure to that described in Example 3 to afford the title compound asan amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ:2.64 (3H,d,J=4.8 Hz), 2.60-2.71 (1H,m), 2.88.(3H,d,J=4.8 Hz), 2.93-3.00 (1H,m), 3.01 (3H,s), 3.10(3H,s), 3.56-3.62(1H,m), 3.97-4.02 (1H,m), 4.28-4.34 (1H,m), 6.64 (1H,dd,J=8.0 Hz,2.0Hz), 6.74 (1H,tri,J=2.0 Hz), 6.91 (1H,dd,J=8.0 Hz,2.0 Hz), 7.14(1H,tri,J=8.1 Hz), 7.23 (1H,dJ=8.0), 7.32 (1H,s), 7.38 (1H,d,J=8.0 Hz),7.46 (1H,tri,J=8.1 Hz)

ms(FAB)m/z:377((M+H)⁺)

EXAMPLE 149 3-[3-(3-Chloro-4-fluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-166)

3-[3-(3-Chloro-4-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 146 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.60-2.70 (1H,m), 2.73 (6H,br), 2.90-3.00(1H,m), 3.01 (3H,s), 3.10 (3H,s), 3.54-3.60 (1H,m), 3.94-3.99 (1H,m),4.26-4.29 (1H,m), 6.59-6.63 (1H,m), 6.76-6.78 (1H,m), 6.99 (1H,tri,J=8.8Hz),. 7.26 (1H,dd,J=8.1 Hz,2.2 Hz), 7.30 (1H,d,J=2.2 Hz), 7.37(1H,dd,J=8.1 Hz,2.2 Hz), 7.46 (1H,tri,J=7.7 Hz).

ms(FAB)m/z:395((M+H)⁺)

EXAMPLE 150 3-[3-(4-Chloro-3-fluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-161)

3-[3-(4-Chloro-3-fluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 147 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.63-2.70 (1H,m), 2.75 (6H,br), 2.93-2.99(1H,m), 3.01 (3H,s), 3.10 (3H,s), 3.56-3.62 (1H,m), 3.96-4.01 (1H,m),4.27-4.31 (1H,m), 6.48-6.57 (2H,m), 7.20 (1H,d,J=8.1 Hz), 7.23(1H,d,J=6.6 Hz), 7.30 (1H,s), 7.37 (1H,d,J=8.1 Hz), 7.46 (1H,tri,J=8.1Hz).

ms(FAB)m/z:395((M+H)⁺)

EXAMPLE 151 (R)-4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-102)

t-Butyl(R)-N-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained from Example 61b and 3,4-difluorophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.51(3H,s), 2.45-2.64(1H,m),2.90-3.05(1H,m), 3.01(3H,s), 3.10(3H,s), 3.50-3.60(1H,m),3.87-3.97(1H,m), 4.27-4.36(1H,m), 6.44-6.52(1H,m), 6.61(1H,ddd,J=11.7Hz,6.6 Hz,2.9 Hz), 7.00(1H,q,J=9.5 Hz), 7.19(2H,d,J=8.8 Hz),7.59(2H,d,J=8.8 Hz) 9.5-10.6(br).

MS (FAB⁺): 365(M+H)⁺.

[α]_(D) ²² −94.8(CHCl₃,C=0.92)

EXAMPLE 152 (R)-4-[3-(3,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-159)

(R)-4-[3-(3-Difluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 151 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.60(3H,brs), 2.55-2.73(1H,br),2.89(3H,brs), 2.82-2.98(1H,br), 3.02(3H,s), 3.11(3H,s),3.45-3.56(1H,br), 3.90-4.00(1H,br), 4.22-4.34(1H,br), 6.40-6.49(1H,m),6.51-6.62(1H,m), 7.01(1H,q,J=9.5 Hz), 7.23(2H,d,J=6.6 Hz),7.56(2H,d,J=6.6 Hz).

MS (FAB+): 379(M+H)+

[α]_(D) ²² −88.9(CHCl3,C=0.98)

EXAMPLE 153 4-[3-(4-Nitrophenylsulfanyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-43)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-nitrothiophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.43 (3H, s), 2.56 (1H, m), 2.82 (2H, m),3.01 (1H, m), 3.02 (3H, s), 3.12 (3H, s), 4.13 (1H, m), 7.23 (4H, m),7.58 (2H, d, J=8.1 Hz), 8.09 (2H, d, J=8.8 Hz)

ms (FAB) m/z: 390 ((M+H)⁺)

EXAMPLE 154 4-[3-(4-Nitrophenylsulfanyl)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-47)

4-[3-(4-Nitrophenylsulfanyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 153 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.59 (3H, m), 2.67 (1H, m), 2.76 (3H, m),2.80 (1H, m), 3.01 (1H, m), 3.04 (3H, s), 3.10 (1H, m), 3.13 (3H, s),4.25 (1H, m), 7.25 (4H, m), 7.53 (2H, d, J=8.1 Hz), 8.12 (2H, d, J=8.8Hz),

ms (FAB) m/z: 404 ((M+H)⁺)

EXAMPLE 155 4-[3-(4-Chlorophenylsulfanyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-42)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-chlorothiophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (400MHz, CDCl₃) δ ppm: 2.40 (3H, s), 2.46 (1H, m), 2.63 (2H, m),2.86 (1H, m), 3.02 (3H, s), 3,11 (3H, s), 4.17 (1H, m), 7.22 (6H, m),7.54 (2H, d, J=8.8 Hz),

ms (FAB) m/z: 379 ((M+H)⁺)

EXAMPLE 156 4-[3-(4-Chlorophenylsulfanyl)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-46)

4-[3-(4-Chlorophenylsulfanyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 155 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.54 (3H, d, J=4.8 Hz), 2.60-2.50 (3H,m), 2.73 (3H, d, J=4.8 Hz), 2.90 (1H, m), 3.03 (3H, s), 3.12 (3H, s),4.21 (1H, m), 7.24 (6H, m), 7.51 (2H, d, J=8.8 Hz),

ms (FAB) m/z: 393 ((M+H)⁺)

EXAMPLE 157 4-[3-(4-Fluorophenylsulfanyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-41)

t-ButylN-[1-(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and 4-fluorothiophenol were treated usingsimilar procedures to those described in Example 7f and 7g to afford thetitle compound as an amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.40 (3H, s), 2.43 (1H, m), 2.60 (2H, m),2.84 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 4.19 (1H, m), 6.98 (2H, t,J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.30 (2H, dd, J=8.8 Hz, 5.9 Hz), 7.54(2H, d, J=8.8 Hz),

ms (FAB) m/z: 363 ((M+H)⁺)

EXAMPLE 158 4-[3-(4-Fluorophenylsulfanyl)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-45)

4-[3-(4-Fluorophenylsulfanyl)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained from Example 157 was treatedusing a similar procedure to that described in Example 3 to afford thetitle compound as an amorphous solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 2.63-2.42 (3H, m), 2.54 (3H, br s), 2.73(3H, br s), 2.86 (1H, m), 3.03 (3H, s), 3.12 (3H, s), 4.21 (1H, m), 7.01(2H, t, J=8.8 Hz), 7.24 (2H, d, J=7.7 Hz), 7.32 (2H, dd, J=8.8 Hz, 5.1Hz), 7.50 (2H, d, J=7.7 Hz),

ms (FAB) m/z: 377 ((M+H)⁺)

EXAMPLE 159 4-[3-(Pyridin-2-yloxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-180)

t-ButylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained from Example 16b and pyridin-2-ol were treated using similarprocedures to those described in Example 48a, 48b and 3 to afford thetitle compound as an amorphous solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.60 (3H, d, J=4.4 Hz), 2.95 (2H, m),3.01 (3H, s), 3.05 (3H, d, J=4.4 Hz), 3.10 (3H, s), 4.17 (1H, br s),4.63 (1H, br s), 4.99 (1H, br s), 7.13 (1H, br d), 7.19 (2H, d, J=7.7Hz), 7.37 (1H, br t), 7.82 (2H, d, J=7.7 Hz), 8.21 (1H, br t), 8.31 (1H,d, J=5.4 Hz),

ms (FAB) m/z: 344 ((M+H)⁺)

EXAMPLE 160 4-[3-(6-Chloropyridin-2-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-124)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and 6-chloropyridine-2-ol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.49 (1H, m), 2.98 (1H, m), 3.01 (3H, s),3.10 (3H, s), 4.41 (1H, br s), 4.47 (1H, br s), 4.61 (1H, br s), 7.05(1H, m), 7.19 (2H, d, J=6.9 Hz), 7.54 (2H, br d), 7.86 (1H, br s), 8.14(1H, br s),

ms (FAB) m/z: 364 ((M+H)⁺)

EXAMPLE 161 4-[3-(6-Chloropyridin-2-yloxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-181)

The title compound was obtained as an amorphous solid using4-[3-(6-chloropyridin-2-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained in Example 160 in a similarmanner to that mentioned in Example 3.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.60 (3H, d, J=3.2 Hz), 2.70 (1H, m),2.84 (3H, d, J=3.2 Hz), 2.97 (1H, m), 3.02 (3H, s), 3.11( 3H, s), 3.94(1H, m), 4.32 (2H, br s), 6.65 (1H, br d, J=8.6 Hz), 7.22 (2H, d, J=7.9Hz), 7.55 (3H, m), 8.02 (1H, br s),

ms (FAB) m/z: 378 ((M+H)⁺)

EXAMPLE 162 (S)-4-[3-(3,4-Difluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-102)

The title compound was obtained as an amorphous solid using t-butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained in step (b) of Example 81 and 3,4-difluorophenol by conductingsuccessively reactions similar to those mentioned in steps (f) and (g)of Example 7.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.51(3H,s), 2.48-2.62(1H,m),2.90-3.05(1H,m), 3.01(3H,s), 3.10(3H,s), 3.50-3.61(1H,m),3.88-3.97(1H,m), 4.27-4.37(1H,m), 6.45-6.55(1H,m), 6.61(1H,ddd,J=11.9Hz,6.5 Hz,3.0 Hz), 7.00(1H,q,J=9.4 Hz), 7.19(2H,d,J=8.5 Hz),7.59(2H,d,J=8.5HZ) 9.4-10.7(br).

MS (FAB⁺) 365(M+H)⁺.

[α]_(D) ²² +94.6(CHCl₃,C=1.05)

EXAMPLE 163 (S)-4-[3-(3,4-Difluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-159)

The title compound was obtained as an amorphous solid using(S)-4-[3-(3,4-difluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained in Example 162 in a similarmanner to that mentioned in Example 3.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.61(3H,brs), 2.60-2.74(1H,br),2.90(3H,brs), 2.84-3.00(1H,br), 3.02(3H,s), 3.11(3H,s),3.42-3.58(1H,br), 3.88-4.00(1H,br), 4.20-4.34(1H,br), 6.40-6.48(1H,m),6.52-6.62(1H,m), 7.01(1H,q,J=9.5 Hz), 7.23(2H,d,J=6.4 Hz),7.56(2H,d,J=6.4 Hz).

MS (FAB+): 379(M+H)⁺

[α]_(D) ²² +86.5(CHCl₃,C=1.06)

EXAMPLE 164 (S)-4-[3-(4-Chlorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate 1/2 fumarate salt (Exemplification compound number1-78)

The title compound was obtained as crystals using(S)-4-[3-(4-chlorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained in Example 82 in a similar manner to that mentioned in Example121.

Melting point: 173-174° C.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.16-2.29(1H,m), 2.39(3H,s),2.46-2.59(1H,m), 2.99(3H,s), 3.08(3H,s), 3.61-3.71(1H,m),3.84-3.94(1H,m), 4.03-4.12(1H,m), 6.71(2H,d,J=8.8 Hz), 6.78(1H,s),7.13(2H,d,J=8.8 Hz), 7.16(2H,d,J=8.8 Hz), 7.39(2H,d,J=8.8 Hz).

MS (FAB+): 363(M+H)⁺

[α]_(D) ²² +78.4(CHCl₃,C=1.03)

EXAMPLE 1654-[3-(4-Dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]benzoic acid(Exemplification compound number 1-99) (a) Benzyl4-[3-(4-dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]benzoate

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and benzyl 4-hydroxybenzoate byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48.

¹H-NMR(500 MHz,CDCl₃) δ ppm: 2.00-2.07 (1H,m), 2.22-2.29 (1H,m), 2.29(3H,s), 3.01 (3H,s), 3.09 (3H,s), 3.76 (1H,t,J=7.5 Hz), 3.84-3.89(1H,m), 4.00 (1H,dt,J=5.5 Hz,10.0 Hz), 5.33 (2H,s), 6.85 (2H,d,J=9.0Hz), 7.07 (2H,d,J=8.5 Hz), 7.27 (2H,d,J=8.5 Hz), 7.32-7.34 (3H,m), 7.44(2H,d,J=8.0 Hz), 8.00 (2H,d,J=9.0 Hz).

(b) 4-[3-(4-Dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]benzoicacid

The crude title compound was synthesized using benzyl4-[3-t-butoxycarbonylamino-3-(4-dimethylcarbamoyloxy)phenylpropyloxy]benzoateobtained in step (a) of Example 165 by conducting a reaction similar tothat mentioned in step (c) of Example 1, from which the title compoundwas obtained as an amorphous solid by washing with ether.

¹H-NMR(400 MHz,CDCl₃) δ ppm 2.18-2.28 (1H,m), 2.38 (3H,s), 2.52-2.62(1H,m), 3.02 (3H,s), 3.11 (3H,s), 3.90-3.98 (1H,m), 4.13-4.22 (2H,m),6.77 (2H,d,J=8.8 Hz), 7.17 (2H,d,J=8.8 Hz), 7.47 (2H,d,J=8.8 Hz), 7.74(2H,d,J=8.8 Hz).

IR(CHCl₃) 2952, 2470, 1716, 1605, 1511, 1389, 1250, 1169, 1036, 1018,851.

EXAMPLE 1664-[3-(4-Dimethylcarbamoyloxy)phenyl-3-dimethylaminopropyloxy]benzoicacid (Exemplification compound number 1-156)

The title compound was obtained as an amorphous solid using benzyl4-[3-t-butoxycarbonylamino-3-(4-dimethylcarmoyloxy)phenylpropyloxy]benzoateobtained in step (a) of Example 165 by conducting successively reactionssimilar to those mentioned in Example 6(b), 3 and 165(b).

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.23-2.36 (1H,m), 2.41 (6H,s), 2.65-2.74(1H,m), 3.03 (3H,s), 3.12 (3H,s), 3.88-3.94 (1H,m), 4.08-4.14 (1H,m),4.27 (1H,dd,J=9.4 Hz,5.0 Hz), 6.79 (2H,d,J=8.8 Hz), 7.20 (2H,d,J=8.8Hz), 7.38 (2H,d,J=8.8 Hz), 7.71 (2H,d,J=8.8 Hz).

IR(CHCl₃) 2962, 1719, 1605, 1510, 1470, 1391, 1251, 1168, 1037, 1017,851.

EXAMPLE 167 4-[3-(6-Nitropyridin-2-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-126)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and 6-nitropyridine-2-ol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.50 (3H, s), 2.68 (1H, m), 3.01 (3H, s),3.05 (1H, m), 3.10 (3H, s), 4.14 (1H, m), 4.25 (1H, m), 4.47 (1H, m),6.78 (1H, d, J=8.6 Hz), 7.19 (2H, d, J=7.8 Hz), 7.58 (2H, d, J=7.8 Hz),8.33 (1H, dd, J=8.6 Hz, 2.9 Hz), 8.96 (1H, d, J=2.9 Hz), 9.95 (1H, brs), 10.30 (1H, br s),

ms (FAB) m/z: 375 ((M+H)⁺)

EXAMPLE 168 4-[3-(6-Nitropyridin-2-yloxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-183)

The title compound was obtained as an amorphous solid using4-[3-(6-nitropyridin-2-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained in Example 167 in a similarmanner to that mentioned in Example 3.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.63 (3H, d, J=4.7 Hz), 2.75 (1H, m),2.82 (3H, d, J=4.7 Hz), 3.01 (1H, m), 3.02 (3H, s), 3.11 (3H, s), 4.13(1H, m), 4.33 (1H, m), 4.45 (1H, m), 6.73 (1H, d, J=9.0 Hz), 7.23 (2H,d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 8.32 (1H, dd, J=9.0 Hz, 2.8 Hz),8.96 (1H, d, J=2.8 Hz),

ms (FAB) m/z: 389 ((M+H)⁺)

EXAMPLE 1694-[3-(6-Trifluoromethylpyridin-2-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-125)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and 6-trifluoromethylpyridine-2-ol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.50 (3H, m), 2.64 (1H, m), 2.99 (1H, m),3.01 (3H, s), 3.10 (3H, s), 4.06 (1H, m), 4.19 (1H, m), 4.40 (1H, m),6.78 (1H, d, J=8.8 Hz), 7.19 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz),7.75 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.83 (1H, s), 9.97 (1H, br s), 10.26(1H, br s),

IR (KBr) cm⁻¹: 2950, 2770, 2700, 1730, 1610, 1390, 1330, 1290, 1220,1180, 1160, 1130

EXAMPLE 1704-[3-(6-Trifluoromethylpyridin-2-yloxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-182)

The title compound was obtained as an amorphous solid using4-[3-(6-trifluoromethylyridin-2-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride obtained in Example 169 in a similarmanner to that mentioned in Example 3.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.88-2.63 (7H, m), 3.00 (1H, m), 3.02(3H, s), 3.11 (3H, s), 4.02 (1H, m), 4.30 (1H, m), 4.38 (1H, m), 5.73(1H, d, J=7.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.74(1H, m), 8.33 (1H, s),

IR (KBr) cm⁻¹: 2930, 2630, 2580, 2510, 2460, 1730, 1610, 1390, 1330,1290, 1220, 1180, 1160, 1130

EXAMPLE 171 Methyl3-[3-(4-dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]-thiophenecarboxylate(Exemplification compound number 1-130)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and methyl3-hydroxythiophenecarboxylate by conducting successively reactionssimilar to those mentioned in steps (a) and (b) of Example 48.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.55 (1H, m), 2.64 (3H, m), 3.01 (3H, s),3.08 (1H, m), 3.09 (3H, s), 3.87 (3H, s), 4.04 (1H, m), 4.30 (1H, m),4.53 (1H, m), 6.78 (1H, d, J=4.9 Hz), 7.18 (2H, d, J=7.8 Hz), 7.48 (3H,m), 9.84 (1H, br s), 10.65 (1H, br s),

ms (FAB) m/z: 393 ((M+H)⁺)

EXAMPLE 172 Methyl3-[3-(4-Dimethylcarbamoyloxy)phenyl-3-dimethylaminopropyloxy]-thiophenecarboxylate(Exemplification compound number 1-187)

The title compound was obtained as an amorphous solid using methyl3-[3-(4-dimethylcarbamoyloxy)phenyl-3-methylaminopropyloxy]-thiophenecarboxylateobtained in Example 171 in a similar manner to that mentioned in Example3.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 2.58 (3H, d, J=4.9 Hz), 2.68 (1H, m),2.93 (1H, m), 3.00 (3H, m), 3.01 (3H, s), 3.10 (3H, s), 3.56 (1H, m),3.86 (3H, s), 4.24 (1H, m), 4.55 (1H, m), 6.67 (1H, d, J=5.4 Hz), 7.19(2H, d, J=8.8Hz), 7.36 (1H, d, J=5.4 Hz), 7.69 (2H, d, J=8.8 Hz),

IR (film) cm⁻¹: 3420, 3100, 3020, 2950, 2660, 2580, 2510, 2460, 1720,1540, 1440, 1390, 1220, 1070

EXAMPLE 173 4-[3-(2-Nitropyridin-4-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-128)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and 2-nitropyridine-4-ol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 2.39 (1H, m), 2.50 (3H, d, J=2.0 Hz),2.64 (1H, m), 2.88 (3H, s), 3.01 (3H, s), 3.94 (1H, m), 4.32 (2H, m),7.18 (2H, d, J=8.8 Hz), 7.32 (1H, d, J=5.9 Hz), 7.51 (2H, d, J=8.8 Hz),8.70 (1H, m), 9.01 (1H, s),

ms (FAB) m/z: 375 ((M+H)⁺)

EXAMPLE 174 4-[3-(4-Methylthiophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-199)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and 4-methylthiophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.41 (3H,s), 2.45-2.64 (2H,m), 2.51 (3H,s),2.90-3.09 (2H,m), 3.00 (3H,s), 3.09 (3H,s), 3.51-3.62 (1H,m), 3.88-3.98(1H,m), 4.28-4.42 (1H,m), 6.72 (2H,d,J=8.8 Hz), 7.18 (2H,d,J=8.4 Hz)7.19 (2H,d,J=8.8 Hz), 7.60 (2H,d,J=8.4 Hz), 9.7-10.2 (1H,br), 10.2-10.5(1H,br).

MS (FAB): 375 (M+H)⁺.

EXAMPLE 175 4-[3-(4-Methylthiophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-200)

The title compound was obtained as an amorphous solid using4-[3-(4-methylthiophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained in Example 174 in a similar manner to that mentioned in Example3.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.42 (3H,s), 2.54-2.74 (1H,m), 2.59(3H,brs), 2.85-2.99 (1H,m), 2.85-2.99 (1H,m), 2.91 (3H,brs), 3.02(3H,s), 3.10 (3H,s), 3.46-3.56 (1H,m), 3.92-4.01 (1H,m), 4.23-4.33(1H,m), 6.69 (2H,d,J=8.7 Hz), 7.16-7.25 (4H,m) 7.58 (2H,d,J=8.4 Hz),12.8 (1H,brs)

MS (FAB): 389(M+H)⁺.

EXAMPLE 176 (S)-4-[3-(4-Methylthiophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-199)

The title compound was obtained as an amorphous solid using t-butyl(S)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained in step (a) of Example 81 and 4-methylthiophenol by conductingsuccessively reactions similar to those mentioned in step (a) of Example48 and steps (d) and (e) of Example 61.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.41 (3H,s), 2.45-2.63 (1H,m), 2.51 (3H,s),2.89-3.07 (1H,m), 3.00 (3H,s), 3.09 (3H,s), 3.50-3.62 (1H,m), 3.86-4.00(1H,m), 4.35 (1H,brs), 6.72 (2H,d,J=8.8 Hz), 7.18 (2H,d,J=8.6 Hz), 7.19(2H,d,J=8.8 Hz), 7.60 (2H,d,J=8.6 Hz), 9.75-10.05 (1H,br) ,10.10-10.45(1H,br).

MS (FAB): 375(M+H)⁺.

EXAMPLE 177 (R)-4-[3-(4-Methylthiophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-199)

The title compound was obtained using t-butyl(R)-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]carbamateobtained in step (b) of Example 61 and 4-methylthiophenol by conductingsuccessively reactions similar to those mentioned in steps (c), (d) and(e) of Example 61.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.41 (3H,s), 2.45-2.63 (1H,m), 2.51 (3H,s),2.89-3.07 (1H,m), 3.00 (3H,s), 3.09 (3H,s), 3.50-3.62 (1H,m), 3.86-4.00(1H,m), 4.35 (1H,brs), 6.72 (2H,d,J=8.8 Hz), 7.18 (2H,d,J=8.6 Hz), 7.19(2H,d,J=8.8 Hz), 7.60 (2H,d,J=8.6 Hz), 9.75-10.05 (1H,br), 10.10-10.45(1H,br).

MS (FAB): 375(M+H)⁺.

EXAMPLE 178 4-[3-(Pentafluorophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-203)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and pentafluorophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm 2.52 (3H,s), 2.40-2.63 (1H,m), 2.90-3.15(1H,m), 3.02 (3H,s), 3.11 (3H,s), 3.69-3.85 (1H,m), 4.20-4.31 (1H,m),4.38 (1H,brs), 7.23( 2H,d,J=8.4 Hz), 7.66 (2H,d,J=8.4 Hz), 9.95 (1H,brs)10.34 (1H,brs)

MS (FAB): 419(M+H)⁺.

EXAMPLE 179 4-[3-(Naphthalen-1-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-205)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and l-naphthylphenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.56 (3H,s), 2.65-2.79 (1H,m), 2.99 (3H,s),3.06 (3H,s), 3.12-3.25 (1H,m), 3.70-3.82 (1H,m), 4.06-4.14 (1H,m),4.41-4.53 (1H,br), 6.56 (1H,d,J=7.5 Hz), 7.15 (2H,d,J=8.5 Hz), 7.22-7.29(1H,m), 7.37 (1H,d,J=8.3 Hz), 7.44-7.51 (2H,m), 7.62 (2H,d,J=8.5 Hz),7.73-7.80 (1H,m), 8.16-8.24 (1H,m), 10.03 (1H,brs), 10.41 (1H,brs).

MS (FAB): 379(M+H)⁺.

EXAMPLE 180 4-[3-(Quinolin-6-yloxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-206)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (b) of Example 16 and 6-hydroxyquinoline by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.54 (3H,s), 2.57-2.73 (1H,m), 2.90-3.14(1H,m), 2.99 (3H,s), 3.07 (3H,s), 3.67-3.78 (1H,m), 4.00-4.10 (1H,m),4.35-4.45 (1H,m), 6.89 (1H,d,J=2.9 Hz), 7.18 (2H,d,J=8.1 Hz), 7.26-7.34(2H,m), 7.63 (2H, d,J=8.1 Hz), 7.96 (2H,d,J=8.8 Hz), 8.73 (1H,dd,J=4.4Hz,1.5 Hz).

MS (FAB): 380(M+H)⁺.

EXAMPLE 181 4-[3-(Pentafluorophenoxy)-1-dimethylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 1-204)

The title compound was obtained as an amorphous solid using4-[3-(pentafluorophenoxy)-1-methylaminopropyl]phenyl dimethylcarbamateobtained in Example 178 in a similar manner to that mentioned in Example3.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.59 (3H,s), 2.60-2.76 (1H,m), 2.88-3.05(1H,m), 2.93 (3H,s), 3.03 (3H,s), 3.12 (3H,s), 3.62-3.73 (1H,m),4.18-4.29 (1H,m), 4.29-4.40 (1H,m), 7.27 (2H,d,J=8.4 Hz), 7.64(2H,d,J=8.4Hz).

MS (FAB): 433(M+H)⁺.

EXAMPLE 182 4-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride (Exemplification compound number 4-12)(a) t-ButylN-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylcarbamate

The title compound was obtained using 2-methyl-4-hydroxybenzaldehyde byconducting successively reactions similar to those mentioned in steps(a)-(e) of Example 7.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 1.51 (9H,s), 1.90-2.04 (1H,m), 2.07-2.21(1H,m), 2.21 (3H,s), 2.44 (3H,s), 3.02 (3H,s), 3.11 (3H,s), 3.50-3.60(2H,m), 3.75 (1H,brs), 5.53-5.60 (1H,m), 7.05 (1H,d,J=7.8 Hz), 7.11-7.13(2H,m).

(b) 4-[3-(4-Nitrophenoxy)-1-dimethylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (a) of Example 182 and 4-nitrophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.21 (3H,s), 2.51 (3H,s), 2.62-2.67 (1H,m),3.02 (3H,s), 2.98-3.09 (1H,m), 3.12 (3H,s), 3.75-3.78 (1H,m), 4.08-4.12(1H,m), 4.26 (1H,d,J=6.6 Hz), 6.86 (2H,d,J=9.1 Hz), 7.14 (1H,d,J=8.1Hz), 7.39 (1H,d,J=8.1 Hz), 7.46 (1H,s), 8.1 5(2H,d,J=9.1 Hz)

MS (FAB) m/z: 388 (M+H)⁺.

EXAMPLE 183(S)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride (Exemplification compound number 4-12)(a) t-Butyl(S)-[1-[(4-dimethylcarbamoyloxy)-3-methylphenyl]-3-hydroxypropyl]carbamate

The title compound was obtained using methyl(S)-3-amino-3-(4-hydroxy-2-methylphenyl)propionate, which wassynthesized using 4-hydroxy-2-methylbenzaldehyde as a starting materialby the procedure described in Tetrahedron: Asymmetry, 2, 183 (1991), byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 61.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.44 (9H, s), 1.71-1.82 (2H, m), 2.16 (1H,br), 2.20 (3H, s), 3.02 (3H, s), 3.12 (3H, s), 3.67 (2H, br), 4.84 (1H,br), 5.00 (1H, br), 7.03 (1H, d, J=8.2 Hz), 7.10-7.13 (2H, m).

[α]_(D) ²² −46 (c 0.90, CHCl₃).

(b) (S)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl(S)-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]carbamateobtained in step (a) of Example 183 and 4-nitrophenol by conductingsuccessively reactions similar to those mentioned in step (a) of Example48 and steps (d) and (e) of Example 61.

¹H NMR(CDCl₃, 400 MHz) δ ppm 2.49 (3H, s), 2.54-2.60 (1H, m), 2.93-2.96(1H, m), 3.02 (3H, s), 3.12 (3H, s), 3.77-3.80 (1H, m), 4.07-4.10 (1H,m), 4.20-4.23 (1H, m), 7.86 (2H, d, J=9.2 Hz), 7.13 (1H, d, J=8.5 Hz),7.37 (1H, d, J=8.5 Hz), 7.43 (1H, s), 8.15 (2H, d, J=9.2 Hz).

MS(FAB) m/z: 388 (M+H)⁺.

[α]_(D) ²² +189 (c 0.95, CHCl₃).

EXAMPLE 184(R)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride (Exemplification compound number 4-12)(a) t-Butyl(R)-[1-[(4-dimethylcarbamoyloxy)-3-methylphenyl]-3-hydroxypropyl]carbamate

The title compound was obtained using methyl(R)-3-amino-3-(4-hydroxy-2-methylphenyl)propionate, which wassynthesized using 4-hydroxy-2-methylbenzaldehyde as a starting materialby the procedure described in Tetrahedron: Asymmetry, 2, 183 (1991), byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 61.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.44 (9H,s), 1.76-1.83 (1H,m), 2.00-2.09(1H,m), 2.21 (3H,s), 3.02 (3H,s), 3.12 (3H,s), 3.69 (2H,brs), 4.83-4.93(2H,m), 7.04 (1H,d,J=8.2 Hz), 7.11-7.13 (2H,m).

[α]_(D) +52.9 (c 0.90, CHCl₃)

(b) (R)-4-[3-(4-Nitrophenoxy)-1-methylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl(R)-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]carbamateobtained in step (a) of Example 184 and 4-nitrophenol by conductingsuccessively reactions similar to those mentioned in step (a) of Example48 and steps (d) and (e) of Example 61.

¹H NMR(CDCl₃, 400 MHz) δ ppm 2.21 (3H,s), 2.52 (3H,s), 2.61-2.67 (1H,m),3.01 (3H,s), 3.01-3.12 (1H,m), 3.12 (3H,s), 3.73-3.78 (1H,m), 4.08-4.13(1H,m), 4.26 (1H,brs), 6.86 (2H,d,J=9.1 Hz), 7.13 (1H,d,J=8.2 Hz), 7.39(1H,d,J=8.2 Hz), 7.47 (1H,s), 8.15 (2H,d,J=9.1 Hz), 9.94 (1H,brs), 10.36(1H,brs).

[α]_(D) −123.4 (c 0.95, CHCl₃)

MS (FAB) m/z: 388(M+H)⁺.

EXAMPLE 185 4-[3-(4-Chlorophenoxy)-1-dimethylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride (Exemplification compound number 4-13)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (a) of Example 182 and 4-chlorophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.21 (3H,s), 2.50 (3H,s), 2.50-2.59 (1H,m),2.92-3.02 (1H,m), 3.02 (3H,s), 3.12 (3H,s), 3.59 (1H,td,J=9.6,4.1 Hz),3.90-3.95 (1H,m), 4.25-4.28 (1H,m), 6.72 (2H,d,J=9.0 Hz), 7.12(1H,d,J=8.3 Hz), 7.17 (2H,d,J=9.0 Hz), 7.39 (1H,dd,J=8.3,1.9 Hz), 7.46(1H,s)

MS (FAB) m/z: 377(M+H)⁺.

EXAMPLE 1864-[3-(4-Methylthiophenoxy)-1-dimethylaminopropyl]-2-methylphenyldimethylcarbamate hydrochloride (Exemplification compound number 4-16)

The title compound was obtained as an amorphous solid using t-butylN-[1-[(4-dimethylcarbamoyloxy)-2-methylphenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (a) of Example 182 and 4-methylthiohenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48.

¹H-NMR(400 MHz,CDCl₃) δ ppm: 2.21 (3H,s), 2.41 (3H,s), 2.50 (3H,s),2.50-2.59 (1H,m), 2.91-3.01 (1H,m), 3.01 (3H,s), 3.12 (3H,s), 3.59(1H,td,J=9.6,4.0 Hz), 3.91-3.96 (1H,m), 4.28 (1H,dd,J=10.3,3.9 Hz), 6.74(2H,d,J=8.8 Hz), 7.12 (1H,d,J=8.3 Hz), 7.19 (2H,d,J=8.8 Hz), 7.39(1H,d,J=8.3 Hz), 7.47 (1H,s).

MS (FAB) m/z: 389(M+H)⁺.

EXAMPLE 187 2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl dimethylcarbamatehydrochloride (Exemplification compound number 4-52) (a) EthylN-[2-(3-methoxyphenyl)-ethyl]-malonate

To a solution of 2-(3-methoxy-phenyl)-ethylamine (1.0 g, 6.6 mmol) indichloromethane (10 ml) were added potassium carbonate (1.1 g, 8.0 mmol)and ethyl malonyl chloride (0.92 ml, 7.2 mmol) at 0° C., and resultingmixture was stirred for 30 minutes at 0° C. under a nitrogen atmosphere.After stirring, water (50 ml) was added, and the resulting mixture wasextracted with dichloromethane (30 ml×2). The organic layer was washedsuccessively with water (30 ml×1) and saturated aqueous sodium chloridesolution (30 ml×1), dried over anhydrous sodium sulfate, filtered, andevaporated in vacuo to afford the crude product. The obtained crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (50:50-33:67) as the eluent toafford the title compound (1.1 g, yield: 63%) as a colorless oil.

¹H-NMR(500 MHz,CDCl₃) δ ppm: 1.26 (3H, t, J=7.5 Hz), 2.81 (2H, t, J=7.0Hz), 3.27 (2H, s), 3.55 (2H, q, J=7.0 Hz), 3.80 (3H, s), 4.17 (2H, q,J=7.5 Hz), 6.78-6.80 (3H, m), 7.08 (1H, br s), 7.22 (1H, t, J=8.0 Hz)

(b) Ethyl (6-methoxy-3,4-dihydro-2H-isoquinolin-1-yliden)-acetate

Ethyl N-[2-(3-methoxy-phenyl)-ethyl]-malonate (20.8g, 78.4 mmol)synthesized in step (a) of Example 187 was dissolved in phosphorusoxychloride (60 ml), and the resulting mixture was stirred for 4 hoursat 80° C. under a nitrogen atmosphere. After stirring, the reactionmixture was poured into ice-cold water (300 ml), neutralized withpotassium carbonate, and extracted with ethyl acetate (300 ml×2). Theorganic layer was washed with saturated aqueous sodium chloride solution(300 ml×1), dried over anhydrous sodium sulfate, filtered, andevaporated in vacuo to afford the crude product. The obtained crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (1:1) as the eluent to afforda yellow oily product (7.56 g) containing the title compound as themajor product.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.30 (3H, t, J=7.5 Hz), 2.88 (2H, t, J=7.0Hz), 3.43 (2H, dt, J=3.0, 7.0 Hz), 3.84 (3H, s), 4.16 (2H, q, J=7.5 Hz),5.08 (1H, s), 6.70 (1H, d, J=2.5 Hz), 6.80 (1H, dd, J=2.5, 9.0 Hz), 7.62(1H, d, J=9.0 Hz), 9.04 (1H, br s).

(c) Ethyl (6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate

To a solution of ethyl(6-methoxy-3,4-dihydro-2H-isoquinolin-1-yliden)-acetate (7.56 g)obtained in step (b) of Example 187 in acetic acid (50 ml) was addedplatinum oxide (400 mg), and the resulting mixture was stirred for 3hours at room temperature under a hydrogen atmosphere. After stirring,the reaction mixture was filtered through celite and evaporated invacuo. The residue obtained was neutralized with 1N aqueous sodiumhydroxide solution and potassium carbonate, and extracted with ethylacetate (300 ml×2). The organic layer was washed with saturated aqueoussodium chloride solution (300 ml×1), dried over anhydrous sodiumsulfate, filtered, and evaporated in vacuo to afford the crude product.The crude product was purified by chromatography on a silica gel columnusing a mixed solvent of ethyl acetate and methanol (1:0-5:1) as theeluent to afford the title compound (4.88 g) as a yellow oil.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.26 (3H, t, J=7.2 Hz), 2.67-2.76 (2H, m),2.80-2.87 (2H, m), 3.01 (1H, ddd, J=5.2, 7.6, 12.4 Hz), 3.19 (1H, dt,J=5.2, 12.4 Hz), 4.17 (2H, q, J=7.2 Hz), 4.41 (1H, dd, J=3.2, 9.6 Hz),6.63 (1H, d, J=2.8 Hz), 6.72 (1H, dd, J=2.8, 8.8 Hz), 7.01 (1H, d, J=8.8Hz).

(d) t-Butyl1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

To a solution of ethyl(6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-acetate (4.88 g, 19.6mmol) synthesized in step (c) of Example 187 in dichloromethane (30 ml)was added 1M solution of boron tribromide in dichloromethane (30 ml) at−78° C. with stirring, and the resulting mixture was stirred for 3 hoursat room temperature under a nitrogen atmosphere. After stirring, water(10 ml) was added, and the resulting mixture was neutralized withsaturated aqueous sodium hydrogen carbonate solution and extracted withdichloromethane (40 ml×2). The organic layer was dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to afford the crudeproduct (2.10 g). To a solution of the crude product (2.10 g) intetrahydrofuran (20 ml) was added di-t-butyl dicarbonate (2.84 g, 13.0mmol), and the resulting mixture was stirred for 1 hour at roomtemperature under a nitrogen atmosphere. After stirring, the reactionmixture was evaporated in vacuo and purified by chromatography on asilica gel column using a mixed solvent of hexane and ethyl acetate(90:10-50:50) as the eluent to afford the title compound (1.72 g, yield:26%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.25 (3H, t, J=8.0 Hz), 1.48 (9H, s),2.59-2.90 (4H, m), 3.23-3.30 (0.5H, m), 3.32-3.42 (0.5H, m), 3.84-3.92(0.5H, m), 4.02-4.10 (0.5H, m), 4.08-4.18 (2H, m), 5.26 (1H, br s), 5.46(0.5H, t, J=7.0 Hz), 5.56 (0.5H, t, J=7.0 Hz), 6.60 (1H, s), 6.62-6.68(1H, m), 7.02 (1H, d, J=8.0 Hz).

(e) t-Butyl6-dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate

To a solution of t-butyl1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate(1.70 g, 5.07 mmol) synthesized in step (d) of Example 187 indimethylformamide (5 ml) were added potassium carbonate (1.03 g, 7.50mmol) and N,N-dimethylcarbamoyl chloride (0.69 ml, 7.5 mmol), and theresulting mixture was stirred for 2.5 hours at room temperature under anitrogen atmosphere. After stirring, water (20 ml) was added, and theresulting mixture was extracted with ethyl acetate (20 ml×2). Theorganic layer was washed with saturated aqueous sodium chloride solution(30 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporatedin vacuo to afford the crude product. The crude product was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (2:1-1:1) as the eluent to afford the title compound(1.97 g, yield: 95%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.25 (3H, t, J=7.0 Hz), 1.47 (9H, s),2.62-2.98 (4H, m), 3.00 (3H, s), 3.08 (3H, s), 3.18-3.26 (0.5H, m),3.32-3.40 (0.5H, m), 3.90-3.92 (0.5H, m), 4.10-4.18 (2.5H, m), 5.53(0.5H, t, J=7.0 Hz), 5.64 (0.5H, t, J=7.0 Hz), 6.89 (1H, s), 6.89-6.97(1H, m), 7.14-7.19 (1H, m).

(f) t-Butyl6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

To a solution of t-butyl6-dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate(1.97 g, 4.84 mmol) synthesized in step (e) of Example 187 intetrahydrofuran (30 ml) was added lithium aluminum hydride (270 mg, 7.2mmol) at −78° C., and the resulting mixture was stirred for 20 minutesat −78° C. and for 20 minutes at 0° C. successively under a nitrogenatmosphere. After stirring, to the reaction mixture were added water(0.3 ml), 15% aqueous sodium hydroxide solution (0.3 ml) and water (0.9ml) in this order with stirring, and the resulting mixture was driedover anhydrous sodium sulfate, filtered, and evaporated in vacuo toafford the crude product. The crude product was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (1:1-0:1) as the eluent to afford the title compound(1.38 g, yield: 78%) as a colorless oil.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.49 (9H, s), 1.74 (1H, t, J=12.4 Hz),2.00-2.10 (1H, m), 2.71 (1H, dt, J=4.4, 16.0 Hz), 2.86-2.94 (1H, m),3.00 (3H, s), 3.09 (3H, s), 3.54 (1H, t, J=11.0 Hz), 3.65 (1H, br), 4.02(1H, dt, J=4.4, 12.4 Hz), 4.12. (0.8H, br), 4.23 (0.2H, br), 5.30 (1H,d, J=12.0 Hz), 6.89 (1H, d, J=2.0 Hz), 6.93 (1H, dd, J=2.0, 8.0 Hz),7.15 (1H, d, J=8.0 Hz).

(g)2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylateobtained in step (f) of Example 187 and 4-nitrophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz): δ 2.19-2.27 (1H, m), 2.89 (3H, d, J=5.2 Hz),3.02 (3H, s), 3.04-3.20 (3H, m), 3.10 (3H, s), 3.32-3.40 (1H, m),3.71-3.80 (1H, m), 4.14-4.20 (1H, m), 4.50 (1H, t, J=6.4 Hz), 4.60-4.65(1H, m), 7.02-7.10 (5H, m), 8.23 (2H, d, J=8.8 Hz).

MS(FAB) m/z: 400 (M+H)⁺.

EXAMPLE 1882-Methyl-1-[2-(4-chloro-3-methylphenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate hydrochloride (Exemplification compound number 4-60)

The title compound was obtained as an amorphous solid using t-butyl6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylateobtained in step (f) of Example 187 and 4-chloro-3-methylphenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48 and Example 3.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 7.24 (1H, d, J=8.8), 7.10 (1H, m), 7.03(2H, m), 6.83 (1H, s), 6.72 (1H, d, J=7.6), 4.53 (1H, br s), 4.35 (1H,br s), 3.98 (1H, br s), 3.75 (1H, br s), 3.35 (1H, br s), 3.15 (1H, m),3.10 (3H, s), 3.02 (3H, s), 2.89 (3H, s), 2.35 (3H, s), 2.16 (1H, br s),1.72 (2H, br s)

MS(FAB) m/z: 403 (M+H)⁺.

EXAMPLE 1892-Methyl-1-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate hydrochloride (Exemplification compound number 4-58)

The title compound was obtained as an amorphous solid using t-butyl6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylateobtained in step (f) of Example 187 and 2-chloro-4-nitrophenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz): δ 2.32-2.44 (1H, m), 2.90 (3H, s), 2.92-3.02(1H, m), 3.02 (3H, s), 3.08-3.22 (2H, m), 3.10 (3H, s), 3.34-3.42 (1H,m), 3.68-3.78 (1H, m), 4.26-4.34 (1H, m), 4.56-4.62 (1H, m), 4.92-5.00(1H, m), 7.05 (1H, d, J=2.4 Hz), 7.09 (1H, dd, J=2.4, 9.0 Hz), 7.16 (1H,d, J=9.0 Hz), 7.28 (1H, d, J=9.0 Hz), 8.19 (1H, dd, J=2.4, 9.0 Hz), 8.32(1H, d, J=2.4 Hz)

MS(FAB) m/z: 433 (M+H)⁺.

EXAMPLE 1902-Methyl-1-(R)-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate hydrochloride (Exemplification compound number 4-60)(a)6-Methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide

To a solution of6-methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoquinoline(1.30 g, 4.05 mmol), synthesized according to the procedure described inJ. Org. Chem. 57, 4732 (1992), and pyridine (0.65 ml, 8.10 mmol) indichloromethane (20 ml) was added dropwise trifluoroacetic anhydride(0.69 ml, 4.86 mmol) under cooling in an ice bath, and the resultingmixture was stirred at room temperature. After confirming thedisappearance of the starting material by thin layer chromatography,saturated aqueous sodium hydrogen carbonate solution was added withstirring, and the resulting mixture was extracted with ethyl acetate.The extract was washed successively with dilute hydrochloric acid andsaturated aqueous sodium chloride solution, dried over anhydrous sodiumsulfate, and evaporated in vacuo. The residue obtained was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (2:1) as the eluent to afford the title compound (1.50g, yield: 88%) as a pale yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm:7.08 (1H, m), 6.79 (1H, m), 6.68 (0.25H,d, J=2.5), 6.64 (0.75H, d, J=2.5), 5.62 (0.75H, dd, J=9.0, 5.5), 5.19(0.25H, m), 4.41 (0.25H, ddd, J=13.5, 6.5, 4.5), 4.01 (0.75H, br d),3.79 (3H, s), 3.59 (3H, m), 3.01 (1H, m) , 2.85 (1H, m), 2.13 (1H, m),2.04 (0.75H, m), 1.92 (0.25H, m), 0.93 (2.25H , s), 0.90 (6.75H, s),0.03 (0.25H, s), 0.06(2.63H, s), 0.05 (2.63H, s)

[α]_(D) ²⁵ −45.4° (c 1.06 CH₂Cl₂)

(b)6-Methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide

To a solution of6-methoxy-1-(R)-(2-t-butyldimethylsilyloxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide(1.14 g, 2.73 mmol) obtained in step (a) of Example 190 in acetonitrile(10 ml) was added dropwise 48% solution of hydrofluoric acid in water(0.5 ml, 13.67 mmol) gradually with stirring under cooling in a waterbath. The resulting mixture was further stirred at room temperature, andafter confirming the disappearance of the starting material by thinlayer chromatography, saturated aqueous sodium hydrogen carbonatesolution was added with stirring, and the resulting mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfateand evaporated in vacuo. The residue obtained was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (2:1) as the eluent to afford the title compound (0.65g, yield: 79%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.11 (1H, d, J=8.5), 6.82 (1H, dd, J=8.5,2.5), 6.65 (1H, d, J=2.5), 5.60 (1H, dd, J=10.8, 3.0), 4.09 (1H, br d),3.79 (3H, s), 3.68 (1H, m), 3.50 (2H, m), 3.04 (1H, m), 2.84 (1H, m),2.16 (1H, m), 1.93 (1H, m)

[α]_(D) ²⁵ −30.00 (c 0.98 CH₂Cl₂)

(c)6-Methoxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide

To a solution of6-methoxy-1-(R)-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide(330 mg, 1.09 mmol) obtained in step (b) of Example 190 and carbontetrabromide (542 mg, 1.63 mmol) in dichloromethane (5 ml) was addedgradually triphenyl phosphine (343 mg, 1.31 mmol) with stirring undercooling in a water bath. The resulting mixture was further stirred atroom temperature, and after confirming the disappearance of the startingmaterial by thin layer chromatography, the reaction mixture wasevaporated in vacuo. The residue obtained was purified by chromatographyon a silica gel column using a mixed solvent of hexane and ethyl acetate(80:20) as the eluent to afford the title compound (390 mg, yield: 98%)as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.10 (1H, m), 6.80 (1H, m), 6.70 (0.15H,d, J=2.5), 6.66 (0.85H, d, J=2.5), 5.63 (0.85H, dd, J=9.3, 5.0), 5.10(0.15H, t, J=7.5), 4.41 (0.85H, ddd, J=13.5, 6.5, 4.5), 4.03 (0.85H, brd), 3.79 (3H, s), 3.64 (1H, m), 3.44 (1H, m), 3.30 (1H, m), 3.02 (1H,m), 2.86 (1H, m), 2.45 (1H, m), 2.36 (1H, m)

[α]_(D) ²⁵ −45.1° (c 1.05 CH₂Cl₂)

(d)6-Hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide

To a solution of6-methoxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide(390 mg, 1.07 mmol) obtained in step (c) of Example 190 indichloromethane (5 ml) was added 1M solution of boron tribromide indichloromethane (2.14 ml, 2.14 mmol) gradually at −78° C. with stirring.The resulting mixture was further stirred at −78° C., and afterconfirming the disappearance of the starting material by thin layerchromatography, saturated aqueous sodium hydrogen carbonate solution wasadded to the reaction mixture, and after raising the temperature toambient temperature, the resulting mixture was extracted with ethylacetate. The extract was washed successively with dilute hydrochloricacid and saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate, and evaporated in vacuo. The residue obtainedwas purified by chromatography on a silica gel column using a mixedsolvent of hexane and ethyl acetate (2:1) as the eluent to afford thetitle compound (280 mg, yield: 75%) as a colorless oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.04 (1H, m), 6.72 (1H, m), 6.65 (0.15H,d, J=2.0), 6.62 (0.85H, d, J=2.0), 5.61 (0.85H, dd, J=9.3, 5.0), 5.10(0.15H, t, J=7.5), 4.37 (0.15H, m), 4.02 (0.85H, br d), 3.63 (1H, m),3.45 (1H, m), 3.33 (1H, m), 2.97 (1H, m), 2.84 (1H, m), 2.45 (1H, m),2.35 (1H, m)

[α]_(D) ²⁵ −60.10 (c 0.94 CH₂Cl₂)

(e)6-Dimethylcarbamoyloxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide

To a solution of6-hydroxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide(270 mg, 0.77 mmol) obtained in step (d) of Example 190 and potassiumcarbonate (268 mg, 1.94 mmol) in dimethylformamide (3 ml) was addeddimethylcarbamyl chloride (0.2 ml, 1.55 mmol) gradually with stirringunder cooling in an ice bath. Subsequently, the resulting mixture wasstirred at 40° C., and after confirming the disappearance of thestarting material by thin layer chromatography, water was added to thereaction mixture, and the resulting mixture was extracted with ethylacetate. The extract was washed with saturated aqueous sodium chloridesolution, dried over anhydrous sodium sulfate and evaporated in vacuo.The residue obtained was purified by chromatography on a silica gelcolumn using a mixed solvent of hexane and ethyl acetate (80:20) as theeluent to afford the title compound (170 mg, yield: 52%) as a colorlessoil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.16 (m, 1H), 6.99 (1H, d, J=8.5), 6.97(0.15H, s), 6.93 (0.85H, s), 5.70 (0.85H, m), 5.16 (0.15H, m), 4.44(0.15H, m), 4.04 (0.85H, br d), 3.62 (1H, m), 3.41 (2H, m), 3.09 (3H,s), 3.05 (1H, m), 3.01 (3H, s), 2.85 (1H, m), 2.37 (2H, m)

[α]_(D) ²⁵ −49.00 (c 0.86 CH₂Cl₂)

(f)6-Dimethylcarbamoyloxy-1-(R)-(2-(4-chloro-3-methylphenoxy)ethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide

To a solution of potassium carbonate (115 mg, 0.83 mmol), potassiumiodide (catalytic amount) and 4-chloro-m-cresol (65 mg, 0.46 mmol) indimethylformamide (2 ml) was added a solution of6-dimethylcarbamoyloxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide(160 mg, 0.38 mmol) obtained in step (e) of Example 190 indimethylformamide (2 ml) gradually with stirring under cooling in an icebath. Subsequently, the resulting mixture was stirred at 100° C., andafter confirming the disappearance of the starting material by thinlayer chromatography, the reaction temperature was cooled to ambienttemperature and water was added to the reaction mixture with stirring.The resulting mixture was extracted with ethyl acetate, and the extractwas washed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and evaporated in vacuo. The residue obtainedwas purified by chromatography on a silica gel column using a mixedsolvent of hexane and ethyl acetate (80:20) as the eluent to afford thetitle compound (154 mg, yield: 84%) as a pale yellow oil.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 7.23 (0.2H, d, J=13.5), 7.20 (0.8H, d,J=9.0), 7.15 (0.8H, d, J=8.5), 7.05 (0.2H, d, J=8.0), 6.96 (2H, m), 6.74(1H, m), 6.64 (1H, m), 5.78 (0.8H, dd, J=9.5, 5.0), 5.29. (0.2H, t,J=7.0), 4.49 (0.2H, m), 4.02 (3H, m), 3.43 (0.2H, m), 3.09 (3H, s), 3.05(1H, m), 3.01 (3H, s), 2.88 (1H, td, J=16.0, 3.5), 2.33 (3H, s), 2.30(2H, m)

[α]_(D) ²⁵ −63.30 (c 0.25 CH₂Cl₂)

(g)1-(R)-(2-(4-Chloro-3-methylphenoxy)-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate

To a solution of6-dimethylcarbamoyloxy-1-(R)-(2-(4-chloro-3-methylphenoxy)ethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide(154 mg, 0.54 mmol) obtained in step (f) of Example 190 in methanol (1ml) was added gradually 1M aqueous solution of potassium carbonate (1ml) with stirring under cooling in a water-bath. The resulting mixturewas stirred at 40° C., and after confirming the disappearance of thestarting material by thin layer chromatography, the reaction temperaturewas cooled to ambient temperature, and saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture with stirring. Theresulting mixture was extracted with ethyl acetate, and the extract waswashed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and evaporated in vacuo. The residue obtainedwas purified by chromatography on a silica gel column using a mixedsolvent of ethyl acetate and methanol (2:1) as the eluent to afford thetitle compound (90 mg, yield: 73%) as a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 7.21(1H, d, J=8.8), 7.12 (1H, d, J=8.8),6.90 (1H, dd, J=8.4, 2.4), 6.86 (1H, d, J=2.4), 6.80 (1H, d, J=2.8),6.69 (1H, dd, J=8.8, 2.8), 4.18 (2H, m), 4.06 (1H, m), 3.18 (1H, m),3.09 (3H, s), 3.01 (3H, s), 3.00 (1H, m), 2.77 (2H, m), 2.33 (3H, s),2.28 (1H, m), 2.14 (1H, m)

[α]_(D) ²⁵ +4.3° (c 0.65 CH₂Cl₂)

(h)2-Methyl-1-(R)-[2-(4-chloro-3-methylphenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using1-(R)-(2-(4-chloro-3-methylphenoxy)-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yldimethylcarbamate obtained in step (g) of Example 190 by conducting areaction similar to that mentioned in Example 3.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 7.24 (1H, d, J=8.8), 7.10 (1H, m), 7.03(2H, m), 6.83 (1H, s), 6.72 (1H, d, J=7.6), 4.53 (1H, br s), 4.35 (1H,br s), 3.98 (1H, br s), 3.75 (1H, br s), 3.35 (1H, br s), 3.15 (1H, m),3.10 (3H, s), 3.02 (3H, s), 2.89 (3H, s), 2.35 (3H, s), 2.16 (1H, br s),1.72 (2H, br s)

[α]_(D) ²⁵ −54.9° (c 0.67 CH₂Cl₂)

EXAMPLE 1912-Methyl-1-[2-(4-chlorophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 5-73)(a) t-Butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

The title compound was obtained as an oily material using2-(4-methoxyphenyl)-ethylamine as the starting material by conductingsuccessively reactions similar to those mentioned in steps (a)-(f) ofExample 187.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.49 (9H, s), 1.77 (1H, t, J=13.5 Hz),2.02-2.11 (1H, m), 2.71 (1H, dt, J=4.0, 15.5 Hz), 2.85-2.92 (1H, m),3.00 (3H, s), 3.09 (3H, s), 3.09-3.16 (1H, m), 3.54 (1H, t, J=12.0 Hz),3.64 (1H, br s), 4.03 (1H, dt, J=4.0, 12.5 Hz), 4.07 (0.8H, br s), 4.25(0.2H, br s), 5.29 (1H, d, J=10.0 Hz), 6.92 (1H, s), 6.93 (1H, d, J=8.0Hz), 7.09 (1H, d, J=8.0 Hz).

(b)2-Methyl-1-[2-(4-chlorophenoxy)-ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylateobtained in step (f) of Example 187 and 4-chlorophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48 and Example 3.

¹H NMR(CDCl₃, 500 MHz): δ 2.14-2.22 (1H, m), 2.89 (3H, d, J=4.5 Hz),2.97 (3H, s), 3.02-(3H, s), 3.02-3.13 (2H, m), 3.21 (1H, br d, J=15.5Hz), 3.31-3.38 (1H, m), 3.71-3.78 (1H, m), 4.03-4.09 (1H, m), 4.37-4.42(1H, m), 4.50 (1H, t, J=6.5 Hz), 6.86 (1H, d, J=2.0 Hz), 6.91 (2H, d,J=8.5 Hz), 7.09 (1H, dd, J=2.0, 8.5 Hz), 7.24 (1H, d, J=8.5 Hz), 7.25(2H, d, J=8.5 Hz).

MS(FAB) m/z: 388 (M+H)⁺.

EXAMPLE 1922-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-132)(a) 4-Formyl-3-hydroxy-phenyl dimethylcarbamate

To a suspension of sodium hydride (5.74 g, 239 mmol), which was preparedfree from mineral oil by washing with hexane, in dimethylformamide (100ml) was added 2,4-dihydroxybenzaldehyde (15.0 g, 109 mmol) at 0° C. withstirring, and the resulting mixture was stirred for 30 minutes at 0° C.under a nitrogen atmosphere. Subsequently, N,N-dimethylcarbamoylchloride (10.1 ml, 110 mmol) was added at 0° C., and the resultingmixture was stirred for 2 hours at room temperature under a nitrogenatmosphere. After stirring, water (300 ml) was added to the reactionmixture, and the resulting mixture was washed with ethyl acetate (200ml×1). The aqueous layer was acidified to pH 1 with concentratedhydrochloric acid and extracted with ethyl acetate (200 ml×3). Theextract was washed successively with water (300 ml×3) and saturatedaqueous sodium chloride solution (200 ml×2), dried over anhydrous sodiumsulfate, filtered, and evaporated in vacuo to afford the crude product.The crude product was purified by chromatography on a silica gel columnusing a mixed solvent of hexane and ethyl acetate (5:1-1:2) as theeluent to afford the title compound (6.78 g, yield: 30%) as a colorlesssolid.

Mp 58-60° C.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 3.02 (3H s), 3.10 (3H, s), 6.77 (1H, d,J=2.0 Hz), 6.82 (1H, dd, J=2.0, 8.0 Hz), 7.53 (1H, d, J=8.0 Hz), 9.84(1H, s), 11.21 (1H, s).

(b) 5-Dimethylcarbamoyloxy-2-formyl-phenyl trifluoromethanesulfonate

To a solution of 4-formyl-3-hydroxy-phenyl dimethylcarbamate (2.60 g,12.4 mmol) synthesized in step (a) of Example 192 in dichloromethane (30ml) were added pyridine (1.61 ml, 20.0 mmol) andtrifluoromethanesulfonic anhydride (2.35 ml, 14.0 mmol) at 0° C. withstirring, and the resulting mixture was stirred for 1 hour at roomtemperature under a nitrogen atmosphere. After stirring, water (20 ml)was added to the reaction mixture, and the resulting mixture wasextracted with dichloromethane (20 ml×2). The organic layer was washedsuccessively with 1N hydrochloric acid (20 ml×1) and saturated aqueoussodium chloride solution (20 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product (4.14 g).The crude product was used for the following reaction without furtherpurification.

¹H NMR(CDCl₃, 500 MHz) δ ppm 3.04 (3H, s), 3.12 (3H, s), 7.31 (1H, d,J=2.0 Hz), 7.35 (1H, dd, J=2.0, 9.0 Hz), 8.00 (1H, d, J=9.0 Hz), 10.21(1H, s).

(c) 4-Formyl-3-vinyl-phenyl dimethylcarbamate

To a solution of 5-dimethylcarbamoyloxy-2-formyl-phenyltrifluoromethanesulfonate (4.13 g, 12.1 mmol) obtained in step (b) ofExample 192 in 1,4-dioxane (15 ml) were addedtetrakis(triphenylphosphine)palladium (693 mg, 0.600 mmol),2,6-di-t-butylphenol (5 mg), lithium chloride (1.54 g, 36.4 mmol) andtributyl(vinyl)tin (4.23 ml, 14.5 mmol) with stirring, and the resultingmixture was stirred for 3 hours at 100° C. under a nitrogen atmosphere.Subsequently, saturated aqueous potassium fluoride solution (5 ml) wasadded to the reaction mixture, and the resulting mixture was stirred for2 hours at room temperature, filtered, and evaporated in vacuo. To theresidue was added water (40 ml), and the resulting mixture was extractedwith ethyl acetate (50 ml×2). The organic layer was washed successivelywith 1N hydrochloric acid (40 ml×1) and saturated aqueous sodiumchloride solution (40 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product. The crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (10:1-1:1) as the eluent toafford the title compound (2.11 g, yield: 79%) as a colorless oil.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 3.04 (3H, s), 3.12 (3H, s), 5.53 (1H, dd,J=1.6, 11.2 Hz), 5.72 (1H, d, J=18.0 Hz), 7.21 (1H, dd, J=2.4, 8.0 Hz),7.33 (1H, d, J=2.4 Hz), 7.53 (1H, dd, J=11.2, 18.0 Hz), 7.84 (1H, d,J=8.0 Hz), 10.24 (1H, s).

(d) Ethyl 3-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-hydroxy-propionate

To a solution of diisopropylamine (1.26 g, 12.5 mmol) in tetrahydrofuran(30 ml) was added 1.6M solution of n-butyllithium in hexane (7.20 ml,11.5 mmol) at −20° C. with stirring, and the resulting mixture wasstirred for 20 minutes at −20° C. under a nitrogen atmosphere.Subsequently, ethyl acetate (1.07 ml, 11.0 mmol) was added at −78° C.,and the resulting mixture was stirred for 20 minutes at −78° C. under anitrogen atmosphere. Subsequently, to the reaction mixture was added asolution of 4-formyl-3-vinyl-phenyl dimethylcarbamate (2.11 g, 9.62mmol) obtained in step (c) of Example 192 in tetrahydrofuran at −78° C.,and the resulting mixture was stirred for 30 minutes at −78° C. under anitrogen atmosphere. After stirring, to the reaction mixture was addedsaturated aqueous ammonium chloride solution (40 ml), and the resultingmixture was extracted with ethyl acetate (40 ml×2). The organic layerwas washed successively with water (40 ml×1) and saturated aqueoussodium chloride solution (40 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product. The crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (1:1-1:2) as the eluent toafford the title compound (2.95 g, yield: 99%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.28 (3H, t, J=7.5 Hz), 2.65 (2H, d, J=6.0Hz), 3.01 (3H, s), 3.10 (3H, s), 3.23-3.25 (1H, m), 4.19 (2H, q, J=7.5Hz), 5.35 (1H, d, J=11.0 Hz), 5.38-5.43 (1H, m), 5.63 (1H, d, J=17.0Hz), 6.99 (1H, dd, J=11.0, 17.0 Hz), 7.05 (1H, d, J=8.5 Hz), 7.20 (1H,s), 7.52 (1H, d, J=8.5 Hz).

(e) 4-(1,3-Dihydroxy-propyl)-3-vinyl-phenyl dimethylcarbamate

To a solution of ethyl3-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-hydroxy-propionate (5.28 g,17.2 mmol) obtained in step (d) of Example 192 in tetrahydrofuran (50ml) was added lithium tetrahydroborate (544 mg, 25.0 mmol) at −20° C.with stirring, and the reaction temperature was raised gradually toambient temperature over one hour under a nitrogen atmosphere. To thereaction mixture were added successively water (20 ml) and 1Nhydrochloric acid (20 ml), and the resulting mixture was extracted withethyl acetate (40 ml×2). The organic layer was dried over anhydroussodium sulfate, filtered; and evaporated in vacuo to afford the crudeproduct. The crude product was purified by chromatography on a silicagel column using mixed solvents of hexane and ethyl acetate (1:1-0:1)and ethyl acetate and methanol (5:1 successively as the eluents toafford the title compound (4.44 g, yield: 97%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.78-1.90 (2H, m), 2.88 (1H, s), 3.00 (3H,s), 3.10 (3H, s), 3.44 (1H, s), 3.77 (2H, br s), 5.14-5.19 (1H, m), 5.32(1H, d, J=11.0 Hz), 5.60 (1H, d, J=17.5 Hz), 6.96 (1H, dd, J=11.0, 17.5Hz), 7.03 (1H, dd, J=2.5, 8.5 Hz), 7.17 (1H, d, J=2.5 Hz), 7.51 (1H, d,J=8.5 Hz).

(f) 4-[3-(t-Butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyldimethylcarbamate

To a solution of 4-(1,3-dihydroxy-propyl)-3-vinyl-phenyldimethylcarbamate (4.44 g, 16.7 mmol) synthesized in step (e) of Example192 in dichloromethane (40 ml) were added triethylamine (4.18 ml, 30.0mmol), t-butyldimethylchlorosilane (4.67 g, 17.0 mmol) and a catalyticamount of 4-dimethylaminopyridine at −0° C. with stirring, and theresulting mixture was stirred for 5 hours at room temperature under anitrogen atmosphere. After stirring, water (30 ml) was added to thereaction mixture, and the resulting mixture was extracted withdichloromethane (40 ml×2). The organic layer was washed successivelywith 1N hydrochloric acid (50 ml×1) and saturated aqueous sodiumchloride solution (50 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product. The crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (2:1-1:1) as the eluent toafford the title compound (5.87 g, yield: 70%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.09 (9H, s), 1.85-1.90 (2H, m), 3.01 (3H,s), 3.10 (3H, s), 3.32 (1H, s), 3.84-3.93 (2H, m), 5.27 (1H, d, J=10.5Hz), 5.28-5.33 (1H, br m), 5.60 (1H, d, J=17.0 Hz), 6.97 (1H, dd,J=10.5, 17.0 Hz), 7.05 (1H, dd, J=2.5, 9.0 Hz), 7.19 (1H, d, J=2.5 Hz),7.38-7.45 (5H, m), 7.51 (1H, d, J=9.0 Hz), 7.69 (4H, d, J=7.0 Hz).

(g)4-[1-Bromo-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyldimethylcarbamate

To a solution of4-[3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyldimethylcarbamate (3.00 g, 5.95 mmol) synthesized in step (f) of Example192 and carbon tetrabromide (3.98 g, 12.0 mmol) in dichloromethane (20ml) was added triphenyl phosphine (3.14 g, 12.0 mmol) at roomtemperature, and the resulting mixture was stirred for 1 hour at roomtemperature under a nitrogen atmosphere. After stirring, the reactionmixture was evaporated in vacuo, and the residue was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (5:1-2:1) as the eluent to afford the title compound(2.62 g, yield: 78%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.05 (9H, s), 2.26-2.33 (1H, m), 2.41-2.48(1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.74 (1H, dt, J=5.0, 9.0 Hz),3.86-3.90 (1H, m), 5.40 (1H, d, J=10.5 Hz), 5.66 (1H, d, J=17.0 Hz),5.70 (1H, dd, J=5.0, 9.0 Hz), 7.04 (1H, dd, J=2.0, 9.0 Hz), 7.10 (1H,dd, J=10.5, 17.0 Hz), 7.19 (1H, d, J=2.0 Hz), 7.33-7.43 (5H, m), 7.46(1H, d, J=9.0 Hz), 7.60 (2H, d, J=7.5 Hz), 7.69 (2H, d, J=7.5 Hz).

(i)4-[1-Allylamino-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyldimethylcarbamate

To a solution of4-[1-bromo-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyldimethylcarbamate (2.62 g, 4.62 mmol) synthesized in step (g) of Example192 in acetonitrile (20 ml) was added allylamine (1.87 ml, 25.0 mmol) atroom temperature, and the resulting mixture was stirred at roomtemperature overnight under a nitrogen atmosphere. After stirring, thereaction mixture was evaporated in vacuo, and the residue was purifiedby chromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (2:1-0:1) as the eluent to afford the title compound(1.82 g, yield: 72%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.06 (9H, s), 1.79-1.84 (2H, m), 3.00 (1H,dd, J=7.0, 16.0 Hz), 3.02 (3H, s), 3.07-3.12 (1H, m), 3.10 (3H, s), 3.65(1H, dt, J=5.0, 11.0 Hz), 3.76 (1H, dt, J=5.0, 11.0 Hz), 4.32 (1H, t,J=6.0 Hz), 5.04 (1H, d, J=11.0 Hz), 5.11 (1H, d, J=17.5 Hz), 5.24 (1H,d, J=11.0 Hz), 5.56 (1H, d, J=17.5 Hz), 5.81-5.89 (1H, m), 7.02 (1H, dd,J=3.0, 9.0 Hz), 7.15 (1H, dd, J=11.0, 17.5 Hz), 7.19 (1H, d, J=3.0 Hz),7.26-7.44 (6H, m), 7.63-7.68 (4H, m).

(j) t-Butylallyl-[3-(t-butyl-diphenyl-silanyloxy)-1-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-propyl]-carbamate

To a solution of4-[l-allylamino-3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyldimethylcarbamate (1.80 g, 3.31 mmol) synthesized in step (i) of Example192 in tetrahydrofuran (20 ml) were added triethylamine (1.12 ml, 8.00mmol) and di-t-butyl dicarbonate (870 mg, 4.00 mmol), and the resultingmixture was stirred for 3 hours at 50° C. under a nitrogen atmosphere.After stirring, the reaction mixture was evaporated in vacuo, and theresidue was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent toafford the title compound (1.90 g, yield: 89%) as a colorless oil.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.04 (9H, s), 1.38 (9H, s), 2.10-2.30 (2H,m), 3.02 (3H, s), 3.11 (3H, s), 3.24-3.60 (2H, br), 3.67 (1H, q, J=B.0Hz), 3.72-3.82 (1H, m), 4.72-4.79 (0.4H, m), 4.79 (0.6H, d, J=9.6 Hz),5.24 (1H, d, J=11.2 Hz), 5.37 (1H, br), 5.51 (1H, br), 5.55 (1H, d,J=17.6 Hz), 6.98 (1H, d, J=8.0 Hz), 7.01 (1H, dd, J=11.2, 17.6 Hz), 7.19(1H, d, J=8.0 Hz), 7.22 (1H, d, J=2.4 Hz), 7.32-7.43 (5H, m), 7.60(1.6H, br s), 7.66 (2.4H, d, J=7.2 Hz).

(k) t-Butyl1-[2-(t-butyl-diphenyl-silanyloxy)-ethyl]-7-dimethylcarbamoyloxy-1,3-dihydro-benzo[c]azepine-2-carboxylate

To a solution of t-butylallyl-[3-(t-butyl-diphenyl-silanyloxy)-1-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-propyl]-carbamate (360 mg, 0.56 mmol) synthesized in step (j) ofExample 192 in dichloromethane (40 ml) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride (47.5 mg, 0.0560 mmol), and the resulting mixture wasstirred for 3 hours at 45° C. under a nitrogen atmosphere. Afterstirring, the reaction mixture was evaporated in vacuo, and the residuewas purified by chromatography on a silica gel column using a mixedsolvent of hexane and ethyl acetate (5:1-2:1) as the eluent to affordthe title compound (330 mg, yield: 96%) as a colorless oil

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.04 (9H, s), 1.38 (9H, s), 2.10-2.30 (2H,m), 3.02 (3H, s), 3.11 (3H, s), 3.24-3.60 (2H, br), 3.67 (1H, q, J=8.0Hz), 3.72-3.82 (1H, m), 4.72-4.79 (0.4H, m), 4.79 (0.6H, d, J=9.6 Hz),5.24 (1H, d, J=11.2 Hz), 5.37 (1H, br), 5.51 (1H, br), 5.55 (1H, d,J=17.6 Hz), 6.98 (1H, d, J=8.0 Hz), 7.01 (1H, dd, J=11.2, 17.6 Hz), 7.19(1H, d, J=8.0 Hz), 7.22 (1H, d, J=2.4 Hz), 7.32-7.43 (5H, m), 7.60(1.6H, br s), 7.66 (2.4H, d, J=7.2 Hz).

(1) t-Butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylate

To a solution of t-butyl1-[2-(t-butyl-diphenyl-silanyloxy)-ethyl]-7-dimethylcarbamoyloxy-1,3-dihydro-benzo[c]azepine-2-carboxylate(1.82 g, 2.96 mmol) synthesized in step (k) of Example 192 intetrahydrofuran (10 ml) was added 1M solution of tetrabutylammoniumfluoride in tetrahydrofuran (6.0 ml, 6.0 mmol) at room temperature, andthe resulting mixture was stirred for 1 hour at room temperature under anitrogen atmosphere. After stirring, water (30 ml) was added to thereaction mixture, and the resulting mixture was extracted with ethylacetate (40 ml×2). The organic layer was washed successively with water(40 ml×1) and saturated aqueous sodium chloride solution (40 ml×1),dried over anhydrous sodium sulfate, filtered, and evaporated in vacuoto afford the crude product. The crude product was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (1:1-0:1) as the eluent to afford the title compound(1.07 g, yield: 96%) as a colorless oil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.30 (5H, s), 1.40 (4H, s), 1.90-2.08 (1H,m), 2.07-2.24 (1H, br), 3.00 (3H, s), 3.09 (3H, s), 3.59 (1H, br s),3.65 (1H, br s), 3.76-3.88 (0.4H, br), 3.98 (0.6H, d, J=19.0 Hz), 4.58(0.6H, d, J=19.0 Hz), 4.78-5.10 (0.4H, br), 4.92-5.20 (0.4H, br), 5.31(0.6H, br t, J=7.5 Hz), 5.77-5.83 (1H, m), 6.32 (0.6H, d, J=11.5 Hz),6.39 (0.4H, d, J=13.0 Hz), 6.92 (1H, dd, J=2.0, 8.0 Hz), 6.95 (1H, s),7.13 (0.6H, d, J=8.0 Hz), 7.25, (0.4H, d, J=8.9 Hz).

(m)2-Methyl-1-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylateobtained in step (1) of Example 192 and 4-nitrophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.12-2.21 (1H, m), 2.60 (3H, s), 2.85-2.93(1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.81 (1H, dd, J=4.4, 19.6 Hz),3.85-3.90 (1H, m), 4.06 (1H, dt, J=5.2, 9.6 Hz), 4.39 (1H, d, J=19.6Hz), 4.77 (1H, d, J=11.6 Hz), 5.85 (1H, ddd, J=3.2, 4.4, 12.4 Hz), 6.36(1H, d, J=12.4 Hz), 6.86 (2H, d, J=8.8 Hz), 7.04 (1H, dd, J=2.4, 8.8Hz), 7.14 (1H, d, J=8.8 Hz), 7.21 (1H, d, J=2.4 Hz), 8.16 (2H, d, J=8.8Hz).

MS(FAB) m/z: 412 (M+H)⁺.

EXAMPLE 1932-Methyl-1-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-137)(a) t-Butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3,4,5-tetrahydro-benzo[c]azepine-2-carboxylate

To a solution of t-butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylate(207 mg, 0.550 mmol) synthesized in step (k) of Example 192 in methanol(10 ml) was added 10% palladium carbon (27 mg), and the resultingmixture was stirred for 1 hour at room temperature. After stirring, thereaction mixture was filtered through celite and evaporated in vacuo toafford the crude product. The crude product was purified bychromatography on a silica gel column using a mixed solvent of ethylacetate and methanol (1:1-0:1) as the eluent to afford the titlecompound (189 mg, yield: 91%) as a colorless oil.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.36 (5.4H, s), 1.45 (3.6H, s), 1.68-1.84(1H, br), 1.86-2.00 (1H, br), 1.88-2.06 (0.4H, br), 2.06-2.18 (0.6H,br), 2.22-2.44 (1H,.br), 2.83 (2H, br s), 3.00 (3H, s), 3.08 (3H, s),3.55-3.68 (1H, br), 3.67 (2H, br s), 3.75-3.90 (1H, br), 5.03-5.18(0.4H, br), 5.38-5.52 (0.6H, br), 6.88 (2H, s), 7.15 (0.4H, br s), 7.24(0.6H, br s).

(b)2-Methyl-1-[2-(2-chloro-4-nitrophenoxy)-ethyl]-1,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.88-2.32 (2H, m), 2.42 (1H, br s),2.60-2.80 (0.4H, br), 2.70 (3H, d, J=4.4 Hz), 2.91 (0.6H, dd, J=5.6,15.6 Hz), 3.01 (1.8H, s), 3.02 (1.2H, s), 3.09 (1.8H, s), 3.10 (1.2H,s), 3.15-3.40 (4H, m), 3.62 (0.4H, t, J=13.6 Hz), 3.82 (0.6H, t, J=13.6Hz), 4.07-4.16 (0.6H, m), 4.30 (1H, dt, J=5.6, 9.2 Hz), 4.53-4.59 (0.4H,m), 4.80 (0.4H, br s), 5.18 (0.6H, br s), 6.93-7.14 (3H, m), 7.17 (0.6H,d, J=8.8 Hz), 7.37 (0.4H, d, J=8.8 Hz), 8.10-8.16 (1H, m), 8.25 (1H, s).

MS(FAB) m/z: 448 (M+H)⁺.

EXAMPLE 1942-Methyl-1-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-140)

The title compound was obtained as an amorphous solid using t-butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylateobtained in step (1) of Example 192 and 4-chloro-3-methylphenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.03-2.12 (1H, m), 2.30 (3H, s), 2.60 (3H,d, J=5.2 Hz), 2.77-2.85 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.65 (1H,dt, J=4.4, 9.6 Hz), 3.78 (1H, dd, J=4.4, 20.0 Hz), 3.85-3.90 (1H, m),4.37 (1H, d, J=17.2 Hz), 4.79 (1H, dt, J=3.6, 12.4 Hz), 5.82 (1H, ddd,J=2.8, 4.4, 12.4 Hz), 6.55 (1H, dd, J=2.8, 8.8 Hz), 6.64 (1H, d, J=12.4Hz), 6.68 (1H, d, J=2.8 Hz), 7.03 (1H, dd, J=2.8, 8.8 Hz), 7.13-7.19(3H, m).

MS(FAB) m/z: 415 (M+H)⁺.

EXAMPLE 195 2-Methyl-1-[2-(2-chloro-4-fluorophenoxy) -ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl dimethylcarbamate hydrochloride(Exemplification compound number 4-139)

The title compound was obtained as an amorphous solid using t-butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylateobtained in step (1) of Example 192 and 2-chloro-4-fluorophenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.07-2.09 (1H,m), 2.61 (3H,s), 2.83-2.92(1H,m), 3.03 (3H,s), 3.11 (3H,s), 3.74-3.82 (2H,m), 4.02-4.07 (1H,m),4.38 (1H,d,J=19.1 Hz), 4.77-4.82 (1H,m), 5.82-5.87 (1H,m), 6.69(1H,d,J=12.7 Hz), 6.82-6.92 (2H,m), 7.06-7.12 (2H,m), 7.18 (1H,d,J=2.3Hz), 7.28 (1H,t,J=8.2 Hz).

MS (FAB) m/z : 419(M+H)⁺.

EXAMPLE 1962-Methyl-1-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-136)

The title compound was obtained as an amorphous solid using t-butyl7-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepine-2-carboxylateobtained in step (1) of Example 192 and 4-methylthiophenol by conductingsuccessively reactions similar to those mentioned in steps (a) and (b)of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.03-2.11 (1H,m), 2.44 (3H,s), 2.60.(3H,s), 2.83 (1H,brs), 3.03 (3H,s), 3.-11 (3H,s), 3.65-3.70 (1H,m), 3.78(1H,d,J=18.9 Hz), 3.89-3.92 (1H,m), 4.38 (1H,d,J=18.9 Hz), 4.79(1H,d,J=10.4 Hz), 5.82 (1H,d,J=12.6 Hz), 6.65 (1H,d,J=12.6 Hz), 6.74(2H,d,J=8.7 Hz), 7.03 (1H,d,J=7.2,1.1 Hz), 7.16 (1H,d,J=8.3 Hz),7.19-7.22 (3H,m). MS (FAB) m/z : 413(M+H)⁺.

EXAMPLE 1972-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-136)(a) 4-Benzyloxy-2-hydoxy-benzaldehyde

To a solution of 2,4-dihydroxybenzaldehyde (50.0 g, 362 mmol) inacetonitrile (350 ml) were added sodium hydrogen carbonate (34.6 g, 412mmol), potassium iodide (6.0 g, 36 mmol), and benzyl chloride (54.0 ml,470 mmol), and the resulting mixture was refluxed for 24 hours under anitrogen atmosphere. At the end of the reaction, 1N hydrochloric acid(400 ml) was added, and the resulting mixture was extracted with ethylacetate (400 ml×2). The organic layer was washed successively with 3%aqueous potassium carbonate solution (300 ml×2), water (300 ml×1), 1Nhydrochloric acid (300 ml×1) and saturated aqueous sodium chloridesolution (300 ml×1), dried over anhydrous sodium sulfate, filtered, andevaporated in vacuo to afford the crude product. The crude product wasrecrystallized from a mixture of t-butyl methyl ether and hexane toafford the title compound (45.9 9, yield: 56%) as pale orange crystals.

Mp 71-72° C.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 5.11 (2H, s), 6.51 (1H, d, J=2.0 Hz), 6.62(1H, dd, J=2.0, 8.5 Hz), 7.35-7.45 (6H, m), 9.72 (1H, s), 11.46 (1H, s).

(b) 4-Benzyloxy-2-methoxymethoxy-benzaldehyde

To a solution of 4-benzyloxy-2-hydoxy-benzaldehyde (44.9 g, 197 mmol)synthesized in step (a) of Example 197 in dichloromethane (200 ml) wereadded diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethylchloride (20.5 ml, 270 mmol) at 0° C. with stirring, and the resultingmixture was stirred overnight at room temperature under a nitrogenatmosphere. After stirring, water (200 ml) was added, and the resultingmixture was extracted with dichloromethane (200 ml×2). The organic layerwas washed successively with water (300 ml×1) and saturated aqueoussodium chloride solution (300 ml×1), dried over anhydrous sodiumsulfate, filtered, and evaporated in vacuo to afford-the crude product.The crude product was purified by chromatography on a silica gel columnusing a mixed solvent of hexane and ethyl acetate (5:1-1:1) as theeluent to afford the title compound (42.2 g, yield: 79%) as a colorlessoil.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 3.51 (3H, s), 5.11(2H, s), 5.26 (2H, s),6.68 (1H, dd, J=2.0, 9.0 Hz), 6.80 (1H, d, J=9.0 Hz), 7.34-7.43 (5H, m),7.81 (1H, d, J=9.0 Hz), 9.72 (1H, s), 11.46 (1H, s).

(c) Ethyl 3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate

To a suspension of 55% sodium hydride dispersion in mineral oil (1.57 g,36.0 mmol) in tetrahydrofuran (100 ml) was added ethyldiethylphosphonoacetate (7.17 g, 32.0 mmol) at 0° C. with stirring, andthe resulting mixture was stirred for 30 minutes at 0° C. under anitrogen atmosphere. Subsequently, a solution of4-benzyloxy-2-methoxymethoxy-benzaldehyde (7.46 g, 27.4 mmol) obtainedin step (b) of Example 197 in tetrahydrofuran was added at 0° C. withstirring, and the resulting mixture was stirred for 2 hours at 0° C.under a nitrogen atmosphere. After stirring, water (200 ml) was added,and the resulting mixture was extracted with ethyl acetate (200 ml×2).The organic layer was washed successively with water (100 ml×1) andsaturated aqueous sodium chloride solution (100 ml×1), dried-overanhydrous sodium sulfate, filtered, and evaporated in vacuo to affordthe crude product. The crude product was purified by chromatography on asilica gel column using a mixed solvent of hexane and ethyl acetate(5:1-1:1) as the eluent to afford the title compound (9.32 g, yield:99%) as a colorless oil.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.32 (3H, t, J=7.2 Hz), 3.47 (3H, s), 4.24(2H, q, J=7.2 Hz), 5.05 (2H s), 5.21 (2H, s), 6.39 (1H, d, J=16.0 Hz),6.62 (1H, dd, J=2.0, 8.8 Hz), 6.81 (1H, d, J=2.0 Hz), 7.30-7.43 (5H, m),7.45 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=16.0 Hz).

(d) Ethyl (3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate

To a solution of (S)-N-benzyl-1-phenylethylamine (4.24 g, 20.1 mmol) intetrahydrofuran (40 ml) was added 1.6 M solution of n-butyllithium inhexane (12.4 ml, 18.9 mmol) at −78° C. with stirring, and the resultingmixture was stirred for 20 minutes at −78° C. under a nitrogenatmosphere. Subsequently, a solution of ethyl3-(4-benzyloxy-2-methoxymethoxy-phenyl)-acrylate (4.32 g, 12.6 mmol)synthesized in Example 3 in tetrahydrofuran was added dropwise at −78°C. with stirring, and the resulting mixture was stirred for 30 minutesat −78° C. under a nitrogen atmosphere. After stirring, a saturatedaqueous ammonium chloride solution (40 ml) was added at −78° C. withstirring, and the resulting mixture was extracted with ethyl acetate (50ml×2). The organic layer was washed with saturated aqueous sodiumchloride solution (50 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product. The crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (10:1-5:1) as the eluent toafford ethyl3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)-amino]-propionate(7.21 g) containing a small amount of (S)-N-benzyl-1-phenylethylamine.

¹H NMR(CDCl₃, 500 MHz) δ ppm: 0.98 (3H, t, J=7.0 Hz), 1.23 (3H, d, J=7.0Hz), 2.60 (1H, dd, J=9.0, 13.5 Hz), 2.73 (1H, dd, J=7.0, 15.0 Hz), 3.47(3H, s), 3.73 (2H, dd, J=14.5, 22.5 Hz), 3.79-3.92 (2H, m), 4.08 (1H, q,J=7.0 Hz), 4.80 (1H, dd, J=6.0, 8.0 Hz), 5.03 (2H, s), 5.15 (2H, dd,J=7.0., 17.0 Hz), 6.61 (1H, dd, J=2.5, 8.5 Hz), 6.83 (1H, d, J=2.5 Hz),7.13-7.44 (16H, m).

Subsequently, to a solution of ethyl3-(4-benzyloxy-2-methoxymethoxy-phenyl)-(3R)-[benzyl-((1S)-phenyl-ethyl)-amino]-propionate (7.21 g) obtained above as a yellow oilin a mixture of methanol/water/acetic acid (80 ml/B ml/4 ml) was added20% palladium hydroxide (1.8 g), and the resulting mixture was stirredfor 4 hours at room temperature under an atmosphere of hydrogen. Afterstirring, the reaction mixture was filtered through celite andevaporated in vacuo to afford the crude product. The crude product waspurified by chromatography on a silica gel column using a mixed solventof ethyl acetate and methanol (1:0-3:1) as the eluent to afford thetitle compound (2.77 g, yield: 67%) as an amorphous solid.

[α]_(D) ²³ −8.0 (c 0.82, MeOH).

¹H NMR(CD₃OD, 400 MHz) δ ppm: 1.20 (3H, t, J=7.6 Hz), 1.90 (3H, s), 2.93(1H, dd, J=6.0, 16.4 Hz), 2.98 (1H, dd, J=8.8, 16.4 Hz), 3.49 (3H, s),4.13 (2H, q, J=7.6 Hz), 4.71 (1H, t, J=7.4 Hz), 5.24 (2H, s) 6.45 (1H,dd, J=2.4, 8.8 Hz), 6.69 (1H, d, J=2.8 Hz), 7.12 (1H, d, J=8.8 Hz).

(e) Ethyl(3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate

To a solution of ethyl(3R)-amino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate acetate(4.26 g, 12.9 mmol) obtained in step (d) of Example 197 in methanol (20ml) were added triethylamine (3.62 ml, 26.0 mmol) and di-t-butyldicarbonate (3.27 g, 15.0 mmol) with stirring, and the resulting mixturewas stirred for 30 minutes at room temperature under a nitrogenatmosphere. After stirring, the reaction mixture was evaporated invacuo, and the residue obtained was purified by chromatography on asilica gel column using a mixed solvent of hexane and ethyl acetate(2:1-1:2) as the eluent to afford the title compound (4.64 g, yield:97%) as a colorless solid. The optical purity of the title compoundobtained was determined to be 98.8% ee by chiral liquid chromatography(Dicel Chiral cel OJ, hexane:isopropanol=95:5, 1 ml/min, R-isomer: 20.48min and S-isomer: 23.68 min).

Mp 82-86° C.

[α]_(D) ²³ +42.3 (c 0.86, CHCl₃)

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.16 (3H, t, J=7.0 Hz), 1.43 (9H, s), 2.79(1H, dd, J=7.0, 14.5 Hz), 2.86 (1H, dd, J=6.0, 14.5 Hz), 3.45 (3H, s),4.05 (2H, q, J=7.0 Hz),4.85-5.20 (3H, m), 5.43 (0.2H, br s), 5.81 (0.8H,d, J=8.0 Hz), 6.28 (1H, d, J=8.0 Hz), 6.50 (1H, br s), 6.57 (1H, br s),6.98 (1H, d, J=8.0 Hz).

(f) Ethyl(3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-propionate

To a solution of ethyl(3R)-t-butoxycarbonylamino-(3R)-(4-hydroxy-2-methoxymethoxy-phenyl)-propionate (2.35 g, 6.36 mmol) synthesized in step (e) of Example 197in dimethylformamide (10 ml) were added potassium carbonate (1.80 g,13.0 mmol) and N,N-dimethylcarbamoyl chloride (0.65 ml, 7.0 mmol) withstirring, and the resulting mixture was stirred for 3 hours at roomtemperature under a nitrogen atmosphere. After stirring, water (30 ml)was added to the reaction mixture, and the resulting mixture wasextracted with ethyl acetate (40 ml×2). The organic layer was washedwith saturated aqueous sodium chloride solution (40 ml×1), dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo to affordthe crude product. The crude product was purified by chromatography on asilica gel column using a mixed solvent of hexane and ethyl acetate(2:1-1:2) as the eluent to afford the title compound (2.73 g, yield:97%) as a colorless oil.

[α]_(D) ²³ +25.3 (c 1.09, CHCl₃)

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.17 (3H, t, J=7.0 Hz), 1.41 (9H, s),2.77-2.89 (2H, m), 2.99 (3H, s), 3.07 (3H, s), 3.49 (3H, s), 4.01-4.10(2H, m), 5.24 (2H, dd, J=7.0, 10.0 Hz), 5.30 (1H, br s), 5.74 (1H, br d,J=9.0 Hz), 6.73 (1H, dd, J=2.0, 9.0 Hz), 6.89 (1H, d, J=2.0 Hz), 7.23(1H, d, J=9.0 Hz).

(g) t-Butyl[(1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-carbamate

To a solution of ethyl(3R)-t-butoxycarbonylamino-(3R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-propionate(4.68 g, 10.6 mmol) synthesized in step (f) of Example 197 intetrahydrofuran (30 ml) was added lithium aluminum hydride (524 mg, 13.8mmol) at −50° C. with stirring, and the resulting mixture was stirredsuccessively for 10 minutes at −50° C. and for 15 minutes at 0° C. undera nitrogen atmosphere. After stirring, to the reaction mixture wereadded water (0.5 ml), 15% aqueous sodium hydroxide solution (0.5 ml) andwater (1.5 ml) at 0° C. in this order, and the resulting mixture wasdried over anhydrous sodium sulfate, filtered, and evaporated in vacuoto afford the crude product. The crude product was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (2:1-0:1) as the eluent to afford the title compound(3.48 g, yield: 82%) as a colorless oil.

[α]_(D) ²³ +48.0 (c 1.09, CHCl₃).

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.43 (9H, s), 1.94 (2H, dt, J=4.8, 6.0Hz), 3.00 (3H, s), 3.08 (3H, s), 3.30 (1H, br s), 3.49 (3H, s),3.61-3.74 (2H, m), 5.06 (1H, q, J=5.6 Hz), 5.23 (2H, dd, J=6.4, 10.8Hz), 5.47 (1H, d, J=9.6 Hz), 6.74 (1H, dd, J=2.4, 8.8 Hz), 6.90 (1H, d,J=2.4 Hz), 7.19 (1H, d, J=8.8 Hz).

(h) 4-[(1R)-Amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxy-phenyldimethylcarbamate

To a solution of t-butyl[(1R)-(4-dimethylcarbamoyloxy-2-methoxymethoxy-phenyl)-3-hydroxypropyl]-carbamate(1.63 g, 4.08 mmol) synthesized in step (g) of Example 197,4-methylthiophenol (660 mg, 4.50 mmol) and triphenylphosphine (1.60 g,6.12 mmol) in tetrahydrofuran (15 ml), was added dropwise 40 wt %solution of diethyl azodicarboxylate in toluene (2.66 g, 6.12 mmol) at0° C. with stirring, and the resulting mixture was stirred for 1 hour atroom temperature under a nitrogen atmosphere. After stirring, thereaction mixture was evaporated in vacuo, and the residue obtained waspurified by chromatography on a silica gel column using a mixed solventof hexane and ethyl acetate (2:1-1:2) as the eluent to afford the crudeproduct (2.74 g) containing hydrazine dicarboxylate. Subsequently, to asolution of the crude product (2.74 g) in methanol (18 ml) was addedconcentrated hydrochloric acid (6 ml), and the resulting mixture wasstirred overnight at room temperature. After stirring, the reactionmixture was neutralized with 15% aqueous sodium hydroxide solution andadjusted to pH 10 with saturated aqueous sodium hydrogen carbonatesolution and then extracted with ethyl acetate (50 ml×2). The organiclayer was dried over anhydrous sodium sulfate, filtered, and evaporatedin vacuo to afford the crude product. The crude product was purified bychromatography on a silica gel column using a mixed solvent of ethylacetate and methanol (1:0-5:1) as the eluent to afford the titlecompound (1.05 g, yield: 69%) as a colorless oil.

[α]_(D) ²³ −66.5 (c 0.77, CHCl₃)

¹H NMR(CDCl₃, 500 MHz) δ ppm: 2.12-2.18 (1H, m), 2.21-2.28 (1H, m), 2.44(3H, s), 2.99 (3H, s), 3.07 (3H, s), 3.89 (1H, dt, J=4.0, 10.0 Hz), 4.00(1H, dt, =5.0, 10.0 Hz), 4.43 (1H, t, J=7.5 Hz), 6.51 (1H, dd, J=2.5,8.0 Hz), 6.60 (1H, d, J=2.5 Hz), 6.82 (2H, d, J=8.5 Hz), 6.86 (1H, d,J=8.0 Hz), 7.25 (2H, d, J=8.5 Hz).

(i) t-Butyl[(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate

To a solution of4-[(1R)-amino-3-(4-methylthiophenoxy)-propyl]-3-hydroxy-phenyldimethylcarbamate (1.05 g, 2.80 mmol) synthesized in step (h) of Example197 in methanol (10 ml) were added triethylamine (0.83 ml, 6.0 mmol) anddi-t-butyl dicarbonate (650 mg, 3.00 mmol), and the resulting mixturewas stirred for 1 hour at room temperature under a nitrogen atmosphere.After stirring, the reaction mixture was evaporated in vacuo, and theresidue obtained was purified by chromatography on a silica gel columnusing a mixed solvent of hexane and ethyl acetate (2:1-0:1) as theeluent to afford the title compound (1.34 g, yield: 100%) as a colorlesssolid.

[α]_(D) ²³ +14.3 (c 0.52, CHCl₃)

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.40 (9H, s), 2.26-2.37 (2H, m), 2.44 (3H,s), 3.00 (3H, s), 3.07 (3H, s), 3.89-3.95 (1H, m), 3.98-4.03 (1H, m),5.00 (1H, dd, J=8.0, 15.2 Hz), 5.25 (1H, br s), 6.63 (1H, dd, J=3.2, 8.0Hz), 6.66 (1H, d, J=3.2 Hz), 6.81 (2H, d, J=8.8 Hz), 7.10 (1H, d, J=8.0Hz), 7.24 (2H, d, J=8.8 Hz).

(j) t-Butyl[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate

To a solution of t-butyl[(1R)-(4-dimethylcarbamoyloxy-2-hydroxy-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate(1.34 g, 2.80 mmol) synthesized in step (i) of Example 197 indichloromethane (10 ml) were added pyridine (0.48 ml, 6.0 mmol) andtrifluoromethanesulfonic anhydride (0.50 ml, 3.0 mmol) at 0° C. withstirring, and the resulting mixture was stirred for 1 hour at roomtemperature under a nitrogen atmosphere. After stirring, water (20 ml)was added to the reaction mixture, and the resulting mixture wasextracted with dichloromethane (20 ml×2). The organic layer was washedsuccessively with 0.5N hydrochloric acid (20 ml×1) and saturated aqueoussodium chloride solution (20 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude triflatederivative (1.48 g).

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.38 (9H, br s), 2.17-2.34 (2H, m), 2.44(3H, s), 3.01 (3H, s), 3.09 (3H, s), 3.97 (2H, t, J=6.0 Hz), 5.13 (1H,dd, J=8.0, 12.5 Hz), 5.44 (1H, br s), 6.82 (2H, d, J=8.5 Hz), 7.14 (1H,d, J=8.5 Hz), 7.15 (1H, s), 7.25 (2H, d, J=8.5 Hz), 7.43 (1H, d, J=8.5Hz).

Subsequently, to a solution of the crude triflate derivative (1.48 g)obtained above in 1,4-dioxane (20 ml) were addedtetrakis(triphenylphosphine)palladium (647 mg, 0.560 mmol),2,6-di-t-butylphenol (5 mg), lithium chloride (356 mg, 8.40 mmol) andtributyl(vinyl)tin (0.88 ml, 3.0 mmol), and the resulting mixture wasstirred for 3 hours at 100° C. under a nitrogen atmosphere.Subsequently, saturated aqueous potassium fluoride solution (10 ml) wasadded, and the resulting mixture was stirred for 2 hours at roomtemperature and then filtered and evaporated in vacuo. To the residueobtained was added water (40 ml), and the resulting mixture wasextracted with ethyl acetate (50 ml×2). The organic layer was washedsuccessively with 1N hydrochloric acid (40 ml×1) and saturated aqueoussodium chloride:solution (40 ml×1), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product. The crudeproduct was purified by chromatography on a silica gel column using amixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent toafford the title compound (1.08 g, yield: 79%) as a colorless oil.

[α]_(D) ²³ −7.7 (c 0.58, CHCl₃).

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.40 (9H, s), 2.18 (2H, br m), 2.44 (3H,s), 3.01 (3H, s), 3.09 (3H, s), 3.84-3.96 (2H, m), 5.23 (1H, br s), 5.31(1H, d, J=10.8 Hz), 5.58 (1H, dd, J=1.2, 16.8 Hz), 6.80 (2H, d, J=8.0Hz), 7.00-7.16 (1H, br m), 7.02 (1H, dd, J=2.8, 8.8 Hz), 7.19-7.28 (4H,m).

(k) t-Butylallyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate

To a solution of t-butyl[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate(1.08 g, 2.22 mmol) synthesized in step (j) of Example 197 indimethylformamide (10 ml) was added sodium hydride (160 mg, 6.66 mmol),being prepared free from mineral oil by washing with hexane, at 0° C.,and the resulting mixture was stirred for 30 minutes at 0° C. under anitrogen atmosphere. Subsequently, allyl bromide (0.57 ml, 6.7 mmol) wasadded at 0° C., and the resulting mixture was stirred for 2 hours atroom temperature under a nitrogen atmosphere. After stirring, water (30ml) was added, and the resulting mixture was extracted with ethylacetate (30 ml×2). The organic layer was washed successively with water(30 ml×1) and saturated aqueous sodium chloride solution (30 ml×1),dried over anhydrous-sodium sulfate, filtered, and evaporated in vacuoto afford the crude product. The-crude product was purified bychromatography on a silica gel column using a mixed solvent of hexaneand ethyl acetate (2:1-1:1) as the eluent to afford the title compound(932 mg, yield: 80%) as a colorless oil.

[α]_(D) ²³ +76.1 (c 0.63, CHCl₃).

¹H NMR(CDCl₃, 500MHz) δ ppm: 1.43 (9H, s), 2.29-2.42 (1H, br m),2.40-2.52 (1H, br m), 2.43 (3H, s), 3.02 (3H, s), 3.11 (3H, s), 3.47(2H, br s), 3.97 (1H, dt, J=6.0, 8.0 Hz), 4.06 (1H, br q, J=8.0 Hz),4.82 (1H, d, J=17.0 Hz), 4.84 (1H, d, J=9.5 Hz), 5.28 (1H, d, J=10.5Hz), 5.48 (1H, br s), 5.58 (1H, d, J=16.5 Hz), 5.67 (1H, br s), 6.82(2H, d, J=8.5 Hz), 7.02 .(1H, dd, J=10.5, 16.5 Hz), 7.04-7.06 (1H,m),7.24-7.26 (3H, m), 7.34 (1H, d, J=7.5 Hz).

(1) t-Butyl7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1,3-dihydro-benzo[c]azepine-2-carboxylate

To a solution of t-butylallyl-[(1R)-(4-dimethylcarbamoyloxy-2-vinyl-phenyl)-3-(4-methylthiophenoxy)-propyl]-carbamate(907 mg, 1.72 mmol) synthesized in step (k) of Example 197 indichlorometane (100 ml) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride (146 mg, 0.172 mmol), and the resulting mixture wasstirred for 3 hours at 45° C. under a nitrogen atmosphere. Afterstirring, the reaction mixture was evaporated in vacuo, and the residuewas purified by chromatography on a silica gel column using a mixedsolvent of hexane and ethyl acetate (2:1-1:1) as the eluent to affordthe title compound (796 mg, yield: 93%) as a colorless oil.

[α]_(D) ²³ −43.8 (c 0.71, CHCl₃).

¹H NMR(CDCl₃, 500 MHz) δ ppm: 1.29 (6H, s), 1.38 (3H, s), 2.27 (1H, brs), 2.36 (1H, br s), 2.44 (3H, s), 3.00 (3H, s), 3.09 (3H, s), 3.77-4.18(3H, br m), 4.74 (0.34H, d, J=16.0 Hz), 4.99 (0.66H, br s), 5.23 (0.66H,br s), 5.35 (0.34H, br s), 5.78 (0.34H, d, J=11.5 Hz), 5.84 (0.66H, d,J=11.5 Hz), 6.35 (1H, d, J=11.5 Hz), 6.80 (0.68H, d, J=7.5 Hz), 6.82(1.32H, d, J=7.5 Hz), 6.88 (1H, br s), 6.96 (1H, s), 7.08 (1H, br s),7.20-7.26 (2H, m).

(m)2-Methyl-(1R)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl7-dimethylcarbamoyloxy-(1R)-[2-(4-methylthiophenoxy)-ethyl]-1,3-dihydro-benzo[c]azepine-2-carboxylateobtained in step (1) of Example 197 by conducting successively reactionssimilar to those mentioned in step (d) of Example 6 and Example 3.

[α]_(D) ²³ −24.2 (c 0.73, CHCl₃).

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.03-2.15 (1H, m), 2.43 (3H, s), 2.53 (3H,s), 2.64-2.76 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.76-3.79 (2H, m),3.92 (1H, quintet, J=5.2 Hz), 4.19 (1H, br s), 4.63 (1H, d, J=7.6 Hz),5.84 (1H, d, J=12.4 Hz), 6.60 (1H, d, J=12.4 Hz), 6.76 (2H, d, J=8.8Hz), 7.00 (1H, dd, J=2.0, 8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.15 (1H, d,J=8.0 Hz), 7.21 (2H, d, J=8.8 Hz).

EXAMPLE 1982-Methyl-(1S)-[2-(4-methylthiophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-136)

The title compound was obtained as an amorphous solid using(R)-N-benzyl-1-phenylethylamine as the starting material instead of(S)-N-benzyl-1-phenylethylamine, by conducting successively reactionssimilar to those mentioned in Example 197.

[α]_(D) ²³ +19.9 (c 0.87, CHCl₃)

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.03-2.15 (1H, m), 2.43 (3H, s), 2.53 (3H,s), 2.64-2.76 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.76-3.79 (2H, m),3.92 (1H, quintet, J=5.2 Hz), 4.19 (1H, br s), 4.63 (1H, d, J=7.6 Hz),5.84 (1H, d, J=12.4 Hz), 6.60 (1H, d, J=12.4 Hz), 6.76 (2H, d, J=8.8Hz), 7.00 (1H, dd, J=2.0, 8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.15 (1H, d,J=8.0 Hz), 7.21 (2H, d, J=8.8 Hz).

EXAMPLE 1992-Methyl-(1S)-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-132)

The title compound was obtained as an amorphous solid using4-nitrophenol as the starting material instead of 4-methylthiophenol byconducting successively reactions similar to those mentioned in Example197.

[α]_(D) ²³ +30.9 (c 0.67, CHCl₃)

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.12-2.21 (1H, m) , 2.60 (3H, s),2.85-2.93 (1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.81 (1H, dd, J=4.4, 19.6Hz), 3.85-3.90 (1H, m), 4.06 (1H, dt, J=5.2, 9.6 Hz), 4.39 (1H, d,J=19.6 Hz), 4.77 (1H, d, J=11.6 Hz), 5.85 (1H, ddd, J=3.2, 4.4, 12.4Hz), 6.36 (1H, d, J=12.4 Hz), 6.86 (2H, d, J=8.8 Hz), 7.04 (1H, dd,J=2.4, 8.8 Hz), 7.14 (1H, d, J=8.8 Hz), 7.21 (1H, d, J=2.4 Hz), 8.16(2H, d, J=8.8 Hz)

EXAMPLE 2002-Methyl-(1S)-[2-(4-nitrophenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yldimethylcarbamate hydrochloride (Exemplification compound number 4-132)

The title compound was obtained as an amorphous solid using4-nitrophenol as the starting material instead of 4-methylthiophenol byconducting successively reactions similar to those mentioned in Example198.

[α]_(D) ²³ −25.0 (c 0.70, CHCl₃)

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.12-2.21 (1H, m), 2.60 (3H, s), 2.85-2.93(1H, m), 3.02 (3H, s), 3.10 (3H, s), 3.81 (1H, dd, J=4.4, 19.6 Hz),3.85-3.90 (1H, m), 4.06 (1H, dt, J=5.2, 9.6. Hz), 4.39 (1H, d, J=19.6Hz), 4.77 (1H, d, J=11.6 Hz), 5.85 (1H, ddd, J=3.2, 4.4, 12.4 Hz), 6.36(1H, d, J=12.4 Hz), 6.86 (2H, d, J=8.8 Hz), 7.04 (1H, dd, J=2.4, 8.8Hz), 7.14 (1H, d, J=8.8 Hz), 7.21 (1H, d, J=2.4 Hz), 8.16 (2H, d, J=8.8Hz).

EXAMPLE 2012-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-8-yldimethylcarbamate hydrochloride (Exemplification compound number 5-160)(a) t-Butyl8-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-carboxylate

The title compound was obtained as an amorphous solid using2,5-dihydroxybenzaldehyde as the starting material by conductingsuccessively reactions similar to those mentioned in steps (a)-(l) ofExample 192.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.29 (9H, s), 1.90-1.98 (1H, m), 2.13-2.14(1H, m), 2.99 (3H, s), 3.12 (3H, s), 3.48-3.56 (2H, m), 3.90-4.04 (1H,m), 4.74-4.83 (1H, m), 5.11-5.19 (1H, m), 5.80 (1H, d, J=12.0 Hz), 6.43(1H, d, J=12.0 Hz), 6.96-7.01 (2H, m), 7.24 (1H, d, J=8.9 Hz).

(b)2-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-8-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl8-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-carboxylateobtained in step (a) of Example 201 and 4-chloro-3-methylphenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48 and Example 3.

¹H NMR(CD₃OD, 400 MHz) δ ppm: 2.19-2.27 (1H, m), 2.31 (3H, s), 2.47-2.56(1H, m), 2.89 (3H, s), 2.95 (3H, s), 3.02 (3H, s), 3.66-3.72 (1H, m),4.01-4.12 (2H, m), 4.25-4.29 (1H, m), 4.80-4.84 (1H, m), 5.82-5.87 (1H,m), 6.70 (1H, dd, J=2.9, 8.7 Hz), 6.78 (1H, d, J=12.7 Hz), 6.82 (1H, d,J=2.9 Hz), 7.02 (1H, d, J=2.4 Hz), 7.20-7.22 (2H, m), 7.47 (1H, d, J=8.4Hz).

MS(FAB) m/z: 415 (M +H)⁺.

EXAMPLE 2022-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-6-yldimethylcarbamate hydrochloride (Exemplification compound number 5-300)(a) t-Butyl6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-carboxylate

The title compound was obtained as an amorphous solid using2,3-dihydroxybenzaldehyde as the starting material by conductingsuccessively reactions similar to those mentioned in steps (a)-(l) ofExample 192.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 1.31 (5.4H, s), 1.42 (3.2H, s), 1.88-2.28(2H, m), 3.02 (3H, s), 3.13 (3H, s), 3.59 (1H, br s), 3.66 (1H, br s),3.85-4.05 (0.4H, br), 3.98 (0.6H, d, J=15.6 Hz), 4.41 (0.6H, d, J=15.6Hz), 4.60-5.00 (0.4H, br), 5.00-5.20 (0.4H, br), 5.35 (0.6H, br t, J=7.2Hz), 5.86-5.91 (1H, m), 6.56 (0.6H, d, J=12.4 Hz), 6.64 (0.-4H, d,J=12.4 Hz), 6.99-7.26 (3H, m)

(b)2-Methyl-[2-(4-chloro-3-methylphenoxy)-ethyl]-2,3-dihydro-1H-benzo[c]azepin-6-yldimethylcarbamate hydrochloride

The title compound was obtained as an amorphous solid using t-butyl6-dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-benzo[c]azepin-2-carboxylateobtained in step (a) of Example 201 and 4-chloro-3-methylphenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48 and Example 3.

¹H NMR(CDCl₃, 400 MHz) δ ppm: 2.14-2.21 (1H, m), 2.30 (3H, s), 2.64 (3H,d, J=4.8 Hz), 2.78-2.89 (1H, m), 3.04 (3H, s), 3.18 (3H, s), 3.65 (1H,dt, J=4.4, 9.6 Hz), 3.78 (1H, d, J=19.2 Hz), 3.89 (1H, dt, J=5.2, 10.4Hz), 4.34 (1H, dd, J=3.6, 19.2 Hz), 4.79 (1H, dt, J=3.6, 11.2 Hz), 5.91(1H, dt, J=3.6, 12.4 Hz), 6.52 (1H, dd, J=2.8, 8.8 Hz), 6.67 (1H, d,J=2.8 Hz), 6.88 (1H, d, J=12.4 Hz), 7.04 (1H, d, J=7.2 Hz), 7.15-7.32(3H, m).

MS(FAB) m/z: 415 (M+H)⁺.

EXAMPLE 203 3-[3-(4-Chloro-3-nitrophenoxy)-1-methylaminopropyl]phenyldimethylcarbamate hydrochloride (Exemplification compound number 2-116)

The title compound was obtained using t-butylN-[1-[(3-dimethylcarbamoyloxy)phenyl]-3-hydroxypropyl]-N-methylcarbamateobtained in step (e) of Example 7 and 4-chloro-3-nitrophenol byconducting successively reactions similar to those mentioned in steps(a) and (b) of Example 48.

¹H-NMR (400 MHz, CDCl₃) δ:7.46 (2H,m), 7.38 (1H, d, J=9.2), 7.30 (2H, d,J=2.8), 7.19 (1H, td, J=7.2, 2.0), 6.99 (1H, dd, J=9.2, 2.4), 4.30 (1H,dd, J=10.4, 4.8), 4.06 (1H, m), 3.73 (1H, td, J=10.9, 4.4), 3.09 (s,3H), 3.03 (m, 1H), 2.98 (s, 3H), 2.63 (1H, m), 2.53 (3H, m)

ms (FAB) m/z: 408 (M+H)⁺.

TEST EXAMPLE TEST EXAMPLE 1 In Vitro Study TEST EXAMPLE 1aAcetylcholinesterase Inhibitory Activity Test

Whole brains of mice were used as a source of acetylcholinesterase.Acetylcholinesterase activity was determined according to a previouslydescribed method (Biochem Pharmacol 7: 88, 1961). Briefly, 10 μl ofdimethylsulfoxide (DMSO)-dissolved test substance was added to 3 ml ofphosphate buffer solution containing the brain homogenate [2990 μl of100 mM phosphate buffer solution (100 mM of Na₂HPO₄ and 100 mM ofNaH₂PO₄, pH=7.4) +10 μl of brain homogenate] and preincubated for 10 minat room temperature. Then 50 μl of dithiobisnitrobenzoate (DTNB)solution (395 mg of DTNB and 150.5 mg of NaHCO₃ dissolved in 100 ml of100 mM phosphate buffer solution) was added to the solution which wasagain preincubated for 20 min at room temperature. Fifty microliters ofacetylthiocholine iodide (ATC) solution (8.676 mg of ATC dissolved in 1ml of distilled water) were added to the solution to initiate theresponse. Immediately and 8 min after the response was started,absorbance (412 nm) was determined and the inhibition rate (%) caused bythe test substance was calculated. Furthermore, the concentration of thetest substance needed to inhibit acetylcholinesterase activity by 50%(IC₅₀) was calculated.

TEST EXAMPLE 1b Serotonin Re-Uptake Inhibitory Activity

Serotonin re-uptake inhibitory activity was determined using synaptosomeprepared from rat whole brains except the cerebellums. Briefly, 10 μl ofDMSO solution-dissolved test substance (control group; DMSO solutionalone) was added to 1 ml of synaptosome and incubated for 5 min at 37°C. (in the control, DMSO alone was added to the synaptosome andincubated at 4° C.). Furthermore, 10 μl of [³H]5-HT solution (finalconcentration: 10 μM as a total concentration of 5-HT, 100 nM as[³H]5-HT) was added and incubated for 5 min at 37° C. Then 4 ml ofice-cold saline was added to stop the response. The response solutionwas filtered, 4 ml of saline was added, and the solution was once againfiltered. Furthermore, 5 ml of Pico-Fluor was added, then ³H levels onfilter papers were counted by a liquid scintillation counter.Concentrations of test compounds to inhibit serotonin re-uptake by 50%(IC₅₀) were calculated.

The results are summarized in Table 6. TABLE 6 IC₅₀ (nM)Acetylcholinesterase Serotonin re-uptake Test Compound No. inhibitoryactivity inhibitory activity Test Compound 16 210 493 Test Compound 30790 594 Test Compound 31 440 323 Test Compound 38 175 199 Test Compound41 79 507 Test Compound 54 670 166 Test Compound 55 280 60 Test Compound61 230 182 Test Compound 62 270 343 Test Compound 68 580 145 TestCompound 70 90 86 Test Compound 76 300 124 Test Compound 81 320 228 TestCompound 82 83 377 Test Compound 89 87 319 Test Compound 95 52 221 TestCompound 102 170 167 Test Compound 104 53 176 Test Compound 124 64 110Test Compound 125 19 841 Test Compound 127 40 856 Test Compound 128 1570 Test Compound 129 64 650 Test Compound 130 42 88 Test Compound 131 57129 Test Compound 136 980 236 Test Compound 152 310 67 Test Compound 162790 594 Test Compound 174 93 85 Test Compound 175 291 380 Test Compound176 88 56 Test Compound 177 201 120 Test Compound 179 372 86 TestCompound 180 111 104 Test Compound 181 198 44 Test Compound 182 50 44Test Compound 183 26 67 Test Compound 184 56 49 Test Compound 185 156170 Test Compound 186 106 62 Test Compound 187 11 940 Test Compound 18853 150 Test Compound 189 6 300 Test Compound 190 12 460 Test Compound191 265 520 Test Compound 192 66 63 Test Compound 193 24 680 TestCompound 194 103 61 Test Compound 195 50 44 Test Compound 196 48 18 TestCompound 197 19 6 Test Compound 199 14 6 Test Compound 200 609 930 TestCompound 202 146 900 Test Compound 203 49 40

As clearly shown in Table 4, the tested compounds of the presentinvention exert remarkable inhibitory activities toward bothacetylcholinesterase activity and serotonin re-uptake activity. Thus thecompounds of the present invention are useful as safe and effectiveremedies.

TEST EXAMPLE 2 Ex Vivo Activity Test TEST EXAMPLE 2aAcetylcholinesterase Inhibiting Activity

Sixty min after oral administration of the test compound to a mouse, thewhole brain except the cerebellum was removed. The removed brain washomogenized in phosphate buffer solution (pH: 8.0) with the volume ofbuffer corresponding to 1.6 times the brain tissue weight. Thehomogenised solution (100 μL) was mixed with acetylthiocholine solution(60 mM, 10 μL) and incubated for 60 sec at 26° C. After centrifugationat 10,000 rpm for 10 min, the supernatant (10 μL) was mixed withdithionitrobenzoic acid solution (10 mM, 200 μL) and left for 20 min atroom temperature for the color to develop. Then the absorbance (415 nm)was determined with a microplate-reader. Relative inhibitory activity(%) of the test compound against the production level of thiocholine inthe brain homogenate of the control group (100%), in which the testcompound was not administered, was calculated.

TEST EXAMPLE 2b Serotonin Transporter Binding Inhibition Test

Sixty min after oral administration of the test compound to a mouse, thewhole brain except the cerebellum was removed. The removed brain washomogenized in 50 mM Tris HCl buffer solution (pH: 7.7) with the volumeof buffer corresponding to 3 times the brain tissue weight. Thehomogenised solution (250 μL) was mixed with [³H]citalopram (NEN LifeScience Products: final concentration 0.77 nM) (1) in the presence offluvoxamine (final concentration: 1 mM) or (2) in the absence offluvoxamine, and incubated for 60 sec at 25° C. After Tris HCl buffersolution (2.5 ml) was added, the solution was centrifuged at 3,000 rpmfor 6 min. The sediment was recovered. After this process was repeatedtwice, the sediment was suspended in 1 mL of the buffer solution andPico-Fluor-40 (4 mL) added. Then the radioactivity was determined with aliquid scintillation counter (ALOKA, LSC-3500). Serotonin transporterprotein binding level was calculated by subtraction of the radioactivityin the presence of citalopram (2) from that in the absence of citalopram(1).

Compounds of the present invention showed potent inhibitory activitiesagainst both acetylcholinesterase activity and serotonin transporterprotein binding in the brains of mice following oral administration.Thus compounds of the present invention are useful as safe and effectiveremedies.

FORMULATION EXAMPLE FORMULATION EXAMPLE 1 Hard Capsules

Each capsule is manufactured by addition of 100 mg of powder of testcompound 1, 100 mg of lactose, 50 mg of cellulose, and 6 mg of magnesiumstearate into a hard gelatin capsule. After washing, the capsule isdried.

FORMULATION EXAMPLE 2 Soft Capsules

Test compound 2 is added into a digestable oily substance, for examplesoybean oil, cottonseed oil, or olive oil, and well mixed. The mixtureis placed into a gelatin capsule with a plunger pump and a soft capsulecontaining 100 mg of active compound obtained. After washing, the softcapsule is dried.

FORMULATION EXAMPLE 3 Tablets

According to conventional methods, the tablet is manufactured using 100mg of test compound 3, 0.2 mg of colloidal silicon dioxide, 5 mg ofmagnesium stearate, 275 mg of crystalline cellulose, 11 mg of starch,and 98.8 mg of lactose.

If desired, the tablet is coated.

FORMULATION EXAMPLE 4 Suspension

A suspension is manufactured containing 100 mg of finely powdered testcompound 4, 10 mg of sodium carboxymethylcellulose, 5 mg of sodiumbenzoate, 1.0 g of sorbitol solution (Japanese Pharmacopoeia), and 0.025ml of vanillin, in 5 ml.

FORMULATION EXAMPLE 5 Cream

A cream formulation is manufactured by addition of 100 mg of finelypowdered test compound 5 into 5 g of cream containing 40% of whitepetrolatum, 3% fine crystallized wax, 10% lanolin, 5% span 20, 0.3%Tween 20, and 41.7% water.

Compounds of the present invention exert inhibitory activities towardsboth acetylcholinesterase activity and selective serotonin re-uptake,and are useful as preventative and/or therapeutic agents for Alzheimer'sdisease, depression, Huntington's chorea, Pick disease, tardivedyskinesia, obsessive-compulsive disorder, or panic disorder.

1. A compound of the formula (I):

wherein R¹ is a C₁-C₆ alkyl group, an amino group, a (C₁-C₆ alkyl)aminogroup, a di(C₁-C₆ alkyl)amino group or a nitrogen-containing saturatedheterocyclic group; R³ is a hydrogen atom or a C₁-C₆ alkyl group; Aromis an unsubstituted or substituted aryl group or an unsubstituted orsubstituted heteroaryl group; wherein the substituted aryl group issubstituted at 1 to 5 positions and the substituted heteroaryl group issubstituted at 1 to 3 positions; and wherein the substituents of thearyl group and of the heteroaryl group are independently selected fromthe group consisting of halogen atom, C₁-C₆ alkyl, halogeno C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃ alkylenedioxy, C₁-C₇ alkanoyl,C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇ alkanoylamino, hydroxyl, mercapto,cyano, nitro and carboxyl; A is a C₁-C₆ alkylene group; R^(a) togetherwith R² is a C₂-C₃ alkylene group containing a double bond; E is asingle bond, an oxygen atom, a sulfur atom or a group of the formula:—NR⁴—, wherein R⁴ is a hydrogen atom or a C₁-C₇ alkanoyl group; X¹ andX² are the same or different and are an oxygen atom or a sulfur atom, ora pharmacologically acceptable salt or ester thereof.
 2. A compound ofthe formula (I):

wherein R¹ is a C₁-C₆ alkyl group, an amino group, a (C₁-C₆ alkyl)aminogroup, a di(C₁-C₆ alkyl)amino group or a nitrogen-containing saturatedheterocyclic group; R³ is a hydrogen atom or a C₁-C₆ alkyl group; Aromis an unsubstituted or substituted aryl group or an unsubstituted orsubstituted heteroaryl group; wherein the heteroaryl group is a 5 to 10memberered heterocyclic group containing from 1 to 3 sulfur atoms,oxygen atoms and/or nitrogen atoms; wherein the substituted aryl groupis substituted at 1 to 5 positions and the substituted heteroaryl groupis substituted at 1 to 3 positions; and wherein the substituents of thearyl group and of the heteroaryl group are independently selected fromthe group consisting of halogen atom, C₁-C₆ alkyl, halogeno C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃ alkylenedioxy, C₁-C₇ alkanoyl,C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇ alkanoylamino, hydroxyl, mercapto,cyano, nitro and carboxyl; A is-a C₁-C₆ alkylene group; R^(a) togetherwith R² is a C₂-C₃ alkylene group containing a double bond; E is anoxygen atom, a sulfur atom or a group of the formula: —NR⁴—, wherein R⁴is a hydrogen atom or a C₁-C₇ alkanoyl group; X¹ and X² are the same ordifferent and are an oxygen atom or a sulfur atom, or apharmacologically acceptable salt or ester thereof.
 3. A compound of theformula (I):

wherein R¹ is a C₁-C₆ alkyl group, an amino group, a (C₁-C₆ alkyl)aminogroup, a di(C₁-C₆ alkyl)amino group or a nitrogen-containing saturatedheterocyclic group; R³ is a hydrogen atom or a C₁-C₆ alkyl group; Aromis an unsubstituted or substituted aryl group or an unsubstituted orsubstituted heteroaryl group; wherein the substituted aryl group issubstituted at 1 to 5 positions and the substituted heteroaryl group issubstituted at 1 to 3 positions; wherein the heteroaryl group is a 5 to10 memberered heterocyclic group containing from 1 to 3 sulfur atoms,oxygen atoms and/or nitrogen atoms; and wherein the substituents of thearyl group and of the heteroaryl group are independently selected fromthe group consisting of halogen atom, C₁-C₆ alkyl, halogeno C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃ alkylenedioxy, C₁-C₇ alkanoyl,C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇ alkanoylamino, hydroxyl, mercapto,cyano, nitro and carboxyl; A is an ethylene group or a propylene group;R^(a) together with R² is a C₁-C₃ alkylene group, which may contain adouble bond in the case of a C₂-C₃ alkylene group; E is an oxygen atom,a sulfur atom or a group of the formula: —NR⁴—, wherein R⁴ is a hydrogenatom or a C₁-C₇ alkanoyl group; X¹ and X² are the same or different andare an oxygen atom or a sulfur atom, or a pharmacologically acceptablesalt or ester thereof.
 4. A compound of the formula (I):

wherein R¹ is a C₁-C₆ alkyl group, an amino group, a (C₁-C₆ alkyl)aminogroup, a di(C₁-C₆ alkyl)amino group or a nitrogen-containing saturatedheterocyclic group; R³is a hydrogen atom or a C₁-C₆ alkyl group; Arom isan unsubstituted aryl group or an aryl group substituted at 1 to 5positions by a substituent or substituents, which are independentlyselected from the group consisting of a halogen atom, C₁-C₆ alkyl group,halogeno C₁-C₆ alkyl group, C₁-C₆ alkoxy group, C₁-C₆ alkylthio group,C₁-C₃ alkylenedioxy group, C₁-C₇ alkanoyl group, C₂-C₇ alkyloxycarbonylgroup, amino group, C₁-C₇ alkanoylamino group, hydroxyl group, mercaptogroup, cyano group, nitro group and carboxyl group; A is a C₁-C₆alkylene group; R^(a) together with R2 is a C₁-C₃, alkylene group, whichmay contain a double bond in the case of a C₂-C₃ alkylene group; E is anoxygen atom, a sulfur atom or a group of the formula: —NR⁴—, wherein R⁴is a hydrogen atom or a C₁-C₇ alkanoyl group; X¹ and X² are the same ordifferent and are an oxygen atom or a sulfur atom, or apharmacologically acceptable salt or ester thereof.
 5. The compound orthe pharmacologically acceptable salt or ester thereof according to anyone of claims 1 to 4, wherein the group of the formula:

is a carbamoyl group, a (C₁-C₄ alkyl)carbamoyl group, a di(C₁-C₄alkyl)carbamoyl group, a thiocarbamoyl group, a (C₁-C₄alkyl)thiocarbamoyl group or a di(C₁-C₄ alkyl)thiocarbamoyl group. 6.The compound or the pharmacologically acceptable salt or ester thereofaccording to any one of claims 1 to 4, wherein the group of the formula:

is a (C₁-C₄ alkyl)carbamoyl group, a di(C₁-C₄ alkyl)carbamoyl group, a(C₁-C₄ alkyl)thiocarbamoyl group or a di(C₁-C₄ alkyl)thiocarbamoylgroup.
 7. The compound or the pharmacologically acceptable salt or esterthereof according to any one of claims 1 to 4, wherein the group of theformula:

is a (C₁-C₄ alkyl)carbamoyl group or a di(C₁-C₄ alkyl)carbamoyl group.8. The compound or the pharmacologically acceptable salt or esterthereof according to any one of claims 1 to 4, wherein the group of theformula:

is a di(C₁-C₄ alkyl)carbamoyl group.
 9. The compound or thepharmacologically acceptable salt or ester thereof according to any oneof claims 1 to 4, wherein the group of the formula:

is a dimethylcarbamoyl group or an ethylmethylcarbamoyl group.
 10. Thecompound or the pharmacologically acceptable salt or ester thereofaccording to any one of claims 1 to 4, wherein the group of the formula:

is a dimethylcarbamoyl group,
 11. The compound or the pharmacologicallyacceptable salt or ester thereof according to any one of claims 1 to 4,wherein R³ is a C₁-C₆ alkyl group.
 12. The compound or thepharmacologically acceptable salt or ester thereof according to any oneof claims 1 to 4, wherein R³ is a methyl group or an ethyl group. 13.The compound or the pharmacologically acceptable salt or ester thereofaccording to any one of claims 1 to 4, wherein R³ is a methyl group. 14.The compound or the pharmacologically acceptable salt or ester thereofaccording to claim 3, wherein R^(a), together with R², is a C₃ alkylenegroup which contains a double bond.
 15. The compound or thepharmacologically acceptable salt or ester thereof according to any oneof claims 1 to 4, wherein Arom is an unsubstituted or substituted arylgroup or an unsubstituted or substituted heteroaryl group; wherein thesubstituted aryl group is substituted at 1 to 3 positions and thesubstituted heteroaryl group is substituted at 1 position; wherein theheteroaryl group is a pyridyl group; and wherein the substituents of thearyl group and of the pyridyl group are independently selected from thegroup consisting of halogen atom, C₁-C₆ alkyl, halogeno C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃ alkylenedioxy, C₁-C₇ alkanoyl,C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇ alkanoylamino, hydroxyl, mercapto,cyano, nitro and carboxyl.
 16. The compound or the pharmacologicallyacceptable salt or ester thereof according to any one of claims 1 to 4,wherein Arom is a phenyl group or a substituted phenyl group; whereinthe substituted phenyl group is substituted at 1 to 3 positions; andwherein the substituents of the phenyl group are independently selectedfrom the group consisting of halogen, C₁-C₆ alkyl, halogeno C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃ alkylenedioxy, C₁-C₇ alkanoyl,C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇ alkanoylamino, hydroxyl, mercapto,cyano, nitro and carboxyl.
 17. The compound or the pharmacologicallyacceptable salt thereof according to any one of claims 1 to 4, whereinArom is a phenyl group substituted at three positions by halogen atomsor a phenyl group substituted at one or two positions by a substituentor substituents, which are independently selected from the groupconsisting of halogen, C₁-C₄ alkyl, C₁-C₄ alkyl substituted by from 1 to3 fluorine atoms, C₁-C₄ alkoxy, C₁-C₄ alkylthio, methylenedioxy,ethylenedioxy, C₁-C₄ alkanoyl, cyano and nitro.
 18. The compound or thepharmacologically acceptable salt thereof according to any one of claims1 to 4, wherein Arom is a phenyl group substituted at three positions bya fluorine atom or a chlorine atom, or is a phenyl group substituted atone or two positions by a substituent or substituents, which areindependently selected from the group consisting of fluorine, chlorine,methyl, trifluoromethyl, methoxy, methylthio, acetyl, cyano and nitro.19. The compound or the pharmacologically acceptable salt thereofaccording to any one of claims 1 to 4, wherein Arom is a phenyl groupsubstituted at three positions by fluorine atoms or is a phenyl groupsubstituted at one or two positions by a substituent or substituents,which are independently selected from the group consisting of fluorine,chlorine, methylthio, acetyl, cyano and nitro.
 20. The compound or thepharmacologically acceptable salt thereof according to any one of claims1 to 4, wherein Arom is a phenyl group substituted at three positions byfluorine atoms or is a phenyl group substituted at one or two positionsby a substituent or substituents, which are independently selected fromthe group consisting of fluorine, chlorine, methylthio and nitro. 21.The compound or the pharmacologically acceptable salt thereof accordingto any one of claims 1 to 4, wherein Arom is a phenyl group substitutedat one position by fluorine, chlorine or nitro or is a phenyl groupsubstituted at two positions by fluorine.
 22. The compound or thepharmacologically acceptable salt thereof according to any one of claims1 to 4, wherein Arom is a 4-fluorophenyl group, a 4-chlorophenyl group,a 4-nitrophenyl group or a 3,4-difluorophenyl group.
 23. The compound orthe pharmacologically acceptable salt or ester thereof according to anyone of claims 1 to 4, wherein A is an ethylene group.
 24. The compoundor the pharmacologically acceptable salt or ester thereof according toany one of claims 1 to 4, wherein E is an oxygen atom.
 25. The compoundor the pharmacologically acceptable salt or ester thereof according toany one of claims 1 to 4, wherein X² is an oxygen atom.
 26. The compoundor the pharmacologically acceptable salt or ester thereof according toany one of claims 1 to 4, wherein X¹ is an oxygen atom.
 27. The compoundor the pharmacologically acceptable salt or ester thereof according toclaims 2 or 3, wherein the group of the formula: R¹—C(═X¹)—X²— isattached at the para position.
 28. The compound or the pharmacologicallyacceptable salt or ester thereof according to any one of claims 1 to 4,wherein R¹ is an amino group, a (C₁-C₆ alkyl)amino group or a di(C₁-C₆alkyl)amino group.
 29. The compound or the pharmacologically acceptablesalt or ester thereof according to any one of claims 1 to 4, wherein R¹is an amino group, a (C₁-C₄ alkyl)amino group or a di(C₁-C₄ alkyl)aminogroup.
 30. The compound or the pharmacologically acceptable salt orester thereof according to any one of claims 1 to 4, wherein R¹ is a(C₁-C₄ alkyl)amino group or a di(C₁-C₄ alkyl)amino group.
 31. Thecompound according to claim 1 or the pharmacologically acceptable saltor ester thereof wherein: R¹ is a (C₁-C₄ alkyl)amino group or a di(C₁-C₄alkyl)amino group; R³ is a hydrogen atom or a C₁-C₆ alkyl group; Arom isan unsubstituted or substituted aromatic hydrocarbon having from 5 to 14carbon carbon atoms, which is unsubstituted or substituted at 1 to 5positions by a substituent or substituents, which are independentlyselected from the group consisting of halogen, C₁-C₆ alkyl, halogenoC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃ alkylenedioxy, C₁-C₇alkanoyl, C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇ alkanoylamino, hydroxyl,mercapto, cyano, nitro and carboxyl; A is an ethylene group; R^(a)together with R² is a C₂-C₃ alkylene group containing a double bond; Eis a single bond, an oxygen atom, a sulfur atom or a group of theformula: —NR⁴—, wherein R⁴ is a hydrogen atom or a C₁-C₇ alkanoyl group;X¹ and X² are oxygen; and the group R¹—C(═X¹)—X²— is in the paraposition.
 32. The compound or the pharmacologically acceptable salt orester thereof according to claim 1, wherein: R¹ is a (C₁-C₄ alkyl)aminogroup or a di(C₁-C₄ alkyl)amino group; R³ is a hydrogen atom or a C₁-C₆alkyl group; Arom is a phenyl group or a phenyl group substituted at 1to 3 positions by a substituent or substituents which are independentlyselected from the group consisting of halogen atom, C₁-C₆ alkyl,halogeno C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₃alkylenedioxy, C₁-C₇ alkanoyl, C₂-C₇ alkyloxycarbonyl, amino, C₁-C₇alkanoylamino, hydroxyl, mercapto, cyano, nitro and carboxyl; A is anethylene group; R^(a) together with R² is a C₂-C₃ alkylene groupcontaining a double bond; E is a single bond, an oxygen atom, a sulfuratom or a group of the formula: —NR⁴—, wherein R⁴ is a hydrogen atom ora C₁-C₇ alkanoyl group; X¹ and X² are oxygen; and the group—X²—C(═X¹)—R¹ is in the para position.
 33. The compound or thepharmacologically acceptable salt or ester thereof according to claim 1,wherein the compound is 2-methyl-1-[2-(4-nitrophenoxy)ethyl]-2,3-dihydro-1H benzo[c]azepin-7-yl dimethylcarbamate.
 34. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of thecompound or the pharmacologically acceptable salt or ester thereofaccording to any one of claims 1 to 4 in combination with apharmaceutically acceptable carrier.
 35. A method of treating orpreventing Alzheimer's disease, depression, Huntington's chorea, Pick'sdisease, tardive dyskinesia, compulsive disorders or panic disorders ina human comprising administering to said human a pharmaceuticallyeffective amount of the compound or the pharmacologically acceptablesalt or ester thereof according to any one of claims 1 to
 4. 36. Themethod according to claim 32, wherein the method is for treating orpreventing Alzheimer's disease.
 37. A method of treating or preventingAlzheimer's disease, depression, Huntington's chorea, Pick's disease,tardive dyskinesia, compulsive disorders or panic disorders in a mammalcomprising administering to a mammal a pharmaceutically effective amountof the compound or the pharmacologically acceptable salt or esterthereof according to any one of claims 1 to 4.